Hamamelitannin analogues and uses thereof

ABSTRACT

The present invention relates to hamamelitannin analogues, pharmaceutical compositions comprising the same, and combinations thereof with anti-microbial agents such as antibiotics or disinfectants. It in particular relates to the use of the compounds, compositions and combinations according to this invention in human or veterinary medicine, more in particular for use in the prevention and/or treatment of bacterial infections, such as  Staphylococcus aureus  infections, in humans or animals.

FIELD OF THE INVENTION

The present invention relates to hamamelitannin analogues,pharmaceutical compositions comprising the same, and combinationsthereof with antimicrobial agents such as antibiotics or disinfectants.It in particular relates to the use of the compounds, compositions andcombinations according to this invention in human or veterinarymedicine, more in particular for use in the prevention and/or treatmentof bacterial infections, such as Staphylococcus aureus infections, inhumans or animals.

BACKGROUND TO THE INVENTION

For a long time, microorganisms such as bacteria, yeasts or fungi wereconsidered non-complex organisms that could easily be eradicated withantimicrobials. However, today we are confronted with an alarming growthof disease-causing microbes that can no longer efficiently be controlledby available antibiotics or antifungals. This phenomenon is generallyreferred to as “antimicrobial resistance” or AMR. Clinicians in manydifferent disciplines are experiencing difficulties to treat patientsdue to ineffective antimicrobials.

The impact of AMR is also evidenced by the problem of infectionsacquired during a stay at a healthcare related institution (hospitals,elderly care) also known as “nosocomial infections”. To combat thespread of AMR, there is an increasing pressure towards a more rationaluse of antibiotics. As a result, almost every Western country haslaunched campaigns to make people aware that misuse of antimicrobialsmakes them ineffective. In fact, the problem of AMR has grown to such adramatic level that the World Health Organization moved it to the top-3of global health risks.

Hence, there is a continuous need for new antimicrobial compositions, oragents that increase sensitivity of micro-organisms towards existingantimicrobials in order to combat the spread of AMR. A particular way ofsensitizing microorganisms for certain antimicrobials is by interferingwith their quorum sensing system.

Microorganisms such as bacteria use quorum sensing to coordinate certainbehaviors such as biofilm formation, virulence, and antibioticresistance, based on the local density of the bacterial population.Quorum sensing (QS) can occur within a single bacterial species as wellas between diverse species, and can regulate different processes, inessence, serving as a simple indicator of population density or thediffusion rate of the cell's immediate environment. Several non-peptidesmall molecules, peptides and proteins have been shown to affect quorumsensing in bacteria and are suitable in the prevention and/or treatmentof bacterial infections. For example hamamelitannin (HAM) or2′,5-di-O-galloyl-D-hamamelose, a natural compound found in the bark andleaves of Hamamelis virginana (witch hazel), was found to act as aquorum sensing inhibitor (QSI) (WO2007147098). HAM interferes with aquorum sensing system in bacteria. It was found that when combining HAMwith an antibiotic, a potentiating or synergistic effect is observed, inparticular HAM increases the susceptibility of bacterial biofilms toantibiotics in vitro as well as in vivo (Brackman et al., 2011).

It is important to emphasize that HAM may not be considered as aclassical antibiotic drug, since it does not exert bactericidal norbacteriostatic effects. HAM probably interferes with mechanisms that areresponsible for the exceptional resistance in biofilms and thus cancause a potentiating or synergistic effect in combination withantibiotics.

The natural HAM product is metabolically unstable and only moderatelyactive, and therefore less preferable in the treatment of microbialinfections. Nevertheless, interesting results obtained with thismolecule provide a conspicuous lead for further optimization, andpresent an opportunity for the development of a novel class ofpharmaceutical compounds, capable of combating microbial infections. Itwas therefore an object of the present invention to provide novelnon-carbohydrate, drug-like HAM analogues with an improved metabolic andchemical stability and increased activity. Furthermore, we havedeveloped an efficient synthetic route to produce these novel compoundsfrom easily available starting materials.

SUMMARY OF THE INVENTION

The invention includes a method of preventing or reducing the growth orproliferation of microorganisms or biofilm-embedded microorganisms, e.g.on a surface of a medical device or in or on subject's body.

In a first aspect, the present invention provides a compound of FormulaI or a stereoisomer, tautomer, racemic, salt, hydrate, or solvatethereof, and optionally a metabolite, pre- or prodrug thereof,

-   Wherein-   X is selected from N—R₉, O and S—R₉;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is absent or selected from —H, —OH, and -halo;-   R₄ is selected from —H, —OH, and -halo;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 substituents selected        from —OH, —C₁₋₆alkyl, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl;    -   or R₇ taken together with R₈ forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   absent or selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or    —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In a particular embodiment, the present invention provides a compoundaccording to formula I,

-   Wherein-   X is selected from N—R₉, O and S—R₉;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ taken together with R₄ forms a dioxolane moiety, which is    optionally substituted with from 1 to 3 substituents selected from    —OH, —C₁₋₆alkyl, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl;    -   or R₇ taken together with R₈ forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   absent or selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₃, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In yet a further particular embodiment, the present invention provides acompound according to formula I,

-   Wherein-   X is selected from N—R₉, O and S—R₉;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is —OH;-   R₄ is —OH;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl;    -   or R₇ taken together with R₈ forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   absent or selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₃, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In a further embodiment, the present invention provides a compoundaccording to formula I,

-   Wherein-   X is selected from N—R₉, O and S—R₉;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is absent or selected from —H, —OH, and -halo;-   R₄ is selected from —H, —OH, and -halo;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 substituents selected        from —OH, —C₁₋₆alkyl, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is —H;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl or R₇ taken together with R₈    forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   absent or selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In another particular embodiment, the present invention provides acompound of formula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is    -   absent or selected from —H, —OH, and -halo;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 substituents selected        from —OH, —C₁₋₆alkyl, and -halo;-   R₄ is selected from —H, —OH, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl or R₇ taken together with R₈    forms Het₄;-   R₉ is absent;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CF₃, or —NR₂₂R₂₃.

In another particular embodiment, the present invention provides acompound of formula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ is    -   selected from —H, and —OH;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 —C₁₋₆alkyl substituents;-   R₄ is —OH;-   R₅ is —H;-   R₆ is selected from —H, and —OH;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅;-   R₈ is —H; or R₇ taken together with R₈ forms Het₄;-   R₉ is absent;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each    of said —C₁₋₆alkyl is optionally and independently substituted with    from 1 to 3 substituents selected from -halo and —Ar₁; in particular    with 1 to 3 Ar₁ substituents;-   R₁₀, is independently selected from —C₁₋₆alkyl, —Ar₂, and Het₂;    wherein each of said —C₁₋₆alkyl is optionally substituted with from    1 to 3 substituents selected -halo and —Ar₂; in particular with 1 to    3 Ar₂ substituents;-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl;-   Ar₁, and Ar₂, are each independently a 5-10 membered aromatic mono-    or bicycle; wherein each of said Ar₁, and Ar₂, is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S, in particular N; wherein each of said    Het₁, Het₂, Het₃ and Het₄ is optionally and independently    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₂R₂₃, and -phenyl;    wherein said phenyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, and phenyl.

In another particular embodiment, the present invention provides acompound of formula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, and —SO₂—R₁₅; wherein    said —C₁₋₆alkyl may be further substituted with —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ and R₄ are —OH; or R₃ taken together with R₄ forms a dioxolane    moiety, which is optionally substituted with from 1 to 3 —C₁₋₆alkyl    substituents;-   R₅ is —H;-   R₆ is selected from —H, and —OH;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅;-   R₈ is —H; or R₇ taken together with R₈ forms Het₄;-   R₉ is absent;-   R₁₃, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each    of said —C₁₋₆alkyl is optionally and independently substituted with    from 1 to 3 substituents selected from -halo and —Ar₁; in particular    with 1 to 3 Ar₁ substituents;-   R₁₀, is independently selected from —Ar₂, and Het₂;-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl; in particular —C₁₋₆alkyl;-   Ar₁, and Ar₂, are each independently a 5-10 membered aromatic mono-    or bicycle; wherein each of said Ar₁, and Ar₂, is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, and Het₃ are each independently a 5-10 membered mono- or    bicyclic heteroaryl comprising from 1 to 3 heteroatoms selected from    N, O and S, in particular N; wherein each of said Het₁, Het₂, and    Het₃ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, and -phenyl.

In a specific embodiment, the invention encompasses a compound asdefined herein, such as any and all compounds represented by formulas Ior II or in Table 1, or stereoisomer, tautomer, racemic, salt,metabolite, pre- or prodrug, hydrate, or solvate thereof, and morespecific a stereoisomer, tautomer, racemic, salt, hydrate, or solvatethereof.

In a specific aspect, the present invention provides a compound asdefined herein, with its ‘X’ and ‘R’ definitions as defined above,wherein the compound has the stereoisomeric configuration as representedin formula II:

The present invention also provides a pharmaceutical compositioncomprising a compound according to the present invention and apharmaceutically acceptable excipient, diluent and/or carrier.

In a further aspect, the present invention provides a combination of acompound according to the present invention with an antimicrobial agent,in particular an antibiotic or disinfectant.

In a specific aspect, the present invention provides a compound,composition or combination according to the present invention, for useas a medicament, more in particular, for use in the prevention and/ortreatment of bacterial infections in humans or animals. In a particularembodiment, said bacterial infection is a Staphylococcus aureusinfection.

In a further aspect, the present invention provides a method for theprevention and/or treatment of bacterial infections; said methodcomprising administering to a subject in need thereof a therapeuticeffective amount of a compound, a composition or a combination asaccording to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

With specific reference to the figures, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of the different embodiments of the present invention only.They are presented in the cause of providing what is believed to be themost useful and readily description of the principles and conceptualaspects of the invention. In this regard no attempt is made to showstructural details of the invention in more detail than is necessary fora fundamental understanding of the invention. The description taken withthe drawings makes it apparent to those skilled in the art how theseveral forms of the invention may be embodied in practice.

FIG. 1: Survival of infected C. elegans nematodes receiving no treatmentor a treatment with one of the compounds (100 μM, 50 μM or 20 μM).Survival was scored 48 h p.i.

FIG. 2: Survival of infected C. elegans nematodes receiving no treatmentor a treatment with vancomycin (20 μg/ml) alone or vancomycin (20 μg/ml)used in combination with the REF or the compounds 159, 171, 173 or 207(50 μM). Survival was scored 48 h p.i.

FIG. 3: Percentage CFU/BF (compared to untreated control) for 24 h oldbiofilms receiving a treatment with an antibiotic alone or incombination with the REF (250 μM). VAN: vancomycin (20 μg/ml), cefo:cefoxitin (70 μg/ml), TOB: tobramycin (1024 μg/ml), CZ: cefazolin (1000μg/ml), CL: cefalonium (1000 μg/ml), DAP: daptomycin (200 μg/ml), LIN:linezolid (20 μg/ml), CX: cefalexin (1000 μg/ml).

FIG. 4: Log CFU/g gland of S. aureus in mouse mammary glands for micereceiving no treatment (CTRL) or a treatment with a selected dose of theREF compound, compound 171 or cefalexin alone or a treatment with acombination of cefalexin and REF or compound 171.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.Each aspect so defined may be combined with any other aspect or aspectsunless clearly indicated to the contrary. In particular, any featureindicated as being preferred or advantageous may be combined with anyother feature or features indicated as being preferred or advantageous.

Unless a context dictates otherwise, asterisks are used herein toindicate the point at which a mono- or bivalent radical depicted isconnected to the structure to which it relates and of which the radicalforms part.

As already mentioned hereinbefore, in a first aspect the presentinvention provides compounds of Formula I,

-   Wherein-   X is selected from N—R₉, O and S;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is absent or selected from —H, —OH, and -halo;-   R₄ is selected from —H, —OH, and -halo;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 substituents selected        from —OH, —C₁₋₆alkyl, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl;    -   or R₇ taken together with R₈ forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In a particular embodiment, the invention relates to a stereoisomer,tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, orsolvate of the compounds provided herein, and especially any and each ofthe compounds represented by Formula I or II and provided in Table 1.More specific, the invention also encompasses a stereoisomer, tautomer,racemic, salt, hydrate, or solvate of said compounds.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless a contextdictates otherwise.

The term “alkyl” by itself or as part of another substituent refers to afully saturated hydrocarbon of Formula C_(x)H_(2x+1) wherein x is anumber greater than or equal to 1. Generally, alkyl groups of thisinvention comprise from 1 to 20 carbon atoms. Alkyl groups may be linearor branched and may be substituted as indicated herein. When a subscriptis used herein following a carbon atom, the subscript refers to thenumber of carbon atoms that the named group may contain. Thus, forexample, C₁₋₄alkyl means an alkyl of one to four carbon atoms. Examplesof alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and itsisomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers,hexyl and its isomers, heptyl and its isomers, octyl and its isomers,nonyl and its isomers; decyl and its isomers. C₁-C₆ alkyl includes alllinear, branched, or cyclic alkyl groups with between 1 and 6 carbonatoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl andits isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers,hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl,cyclopentylmethylene, and cyclohexyl.

The term “optionally substituted alkyl” refers to an alkyl groupoptionally substituted with one or more substituents (for example 1 to 4substituents, for example 1, 2, 3, or 4 substituents or 1 to 2substituents) at any available point of attachment. Non-limitingexamples of such substituents include halo, hydroxyl, carbonyl, nitro,amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl,cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid,acylamino, alkyl esters, carbamate, thioamido, urea, sulfonamido and thelike.

The term “cycloalkyl” by itself or as part of another substituent is acyclic alkyl group, that is to say, a monovalent, saturated, orunsaturated hydrocarbyl group having 1, 2, or 3 cyclic structures.Cycloalkyl includes all saturated or partially saturated (containing 1or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, includingmonocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyl groups maycomprise 3 or more carbon atoms in the ring and generally, according tothis invention comprise from 3 to 15 atoms. The further rings ofmulti-ring cycloalkyls may be either fused, bridged and/or joinedthrough one or more spiro atoms. Cycloalkyl groups may also beconsidered to be a subset of homocyclic rings discussed hereinafter.Examples of cycloalkyl groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, adamantanyl and cyclodecyl with cyclopropylbeing particularly preferred. An “optionally substituted cycloalkyl”refers to a cycloalkyl having optionally one or more substituents (forexample 1 to 3 substituents, for example 1, 2, 3 or 4 substituents),selected from those defined above for substituted alkyl. When the suffix“ene” is used in conjunction with a cyclic group, hereinafter alsoreferred to as “Cycloalkylene”, this is intended to mean the cyclicgroup as defined herein having two single bonds as points of attachmentto other groups. Cycloalkylene groups of this invention preferablycomprise the same number of carbon atoms as their cycloalkyl radicalcounterparts.

Where alkyl groups as defined are divalent, i.e., with two single bondsfor attachment to two other groups, they are termed “alkylene” groups.Non-limiting examples of alkylene groups includes methylene, ethylene,methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene,1,2-dimethylethylene, pentamethylene and hexamethylene. Similarly, wherealkenyl groups as defined above and alkynyl groups as defined above,respectively, are divalent radicals having single bonds for attachmentto two other groups, they are termed “alkenylene” and “alkynylene”respectively.

Generally, alkylene groups of this invention preferably comprise thesame number of carbon atoms as their alkyl counterparts. Where analkylene or cycloalkylene biradical is present, connectivity to themolecular structure of which it forms part may be through a commoncarbon atom or different carbon atom, preferably a common carbon atom.To illustrate this applying the asterisk nomenclature of this invention,a C₃ alkylene group may be for example *—CH₂CH₂CH₂—*, *—CH(—CH₂CH₃)—*,or *—CH₂CH(—CH₃)—*. Likewise a C₃ cycloalkylene group may be

The terms “heterocyclyl” or “heterocyclo” as used herein by itself or aspart of another group refer to non-aromatic, fully saturated orpartially unsaturated cyclic groups (for example, 3 to 13 membermonocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ringsystems, or containing a total of 3 to 10 ring atoms) which have atleast one heteroatom in at least one carbon atom-containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, 3or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/orsulfur atoms, where the nitrogen and sulfur heteroatoms may optionallybe oxidized and the nitrogen heteroatoms may optionally be quaternized.The heterocyclic group may be attached at any heteroatom or carbon atomof the ring or ring system, where valence allows. The rings ofmulti-ring heterocycles may be fused, bridged and/or joined through oneor more spiro atoms. An optionally substituted heterocyclic refers to aheterocyclic having optionally one or more substituents (for example 1to 4 substituents, or for example 1, 2, 3 or 4), selected from thosedefined above for substituted aryl.

Exemplary heterocyclic groups include piperidinyl, azetidinyl,imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl,succinimidyl, 3H-indolyl, isoindolinyl, chromenyl, isochromanyl,xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl,piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl,dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, phthalazinyl,oxetanyl, thietanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl,2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl,1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl,2H-1,5,2-dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl,tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl, and morpholinyl.

The term “aryl” as used herein refers to a polyunsaturated, aromatichydrocarbyl group having a single ring (i.e. phenyl) or multiplearomatic rings fused together (e.g. naphthalene or anthracene) or linkedcovalently, typically containing 6 to 10 atoms; wherein at least onering is aromatic. The aromatic ring may optionally include one to threeadditional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fusedthereto. Aryl is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems enumerated herein. Non-limitingexamples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1- or2-naphthyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1-2-, 3-, 4-, or5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1-, 2-, 3-, 4-, or10-phenanthryl, 1- or 2-pentalenyl, 1, 2-, 3-, or 4-fluorenyl, 4- or5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl,1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl,dibenzo[a,d]cylcoheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.

The aryl ring can optionally be substituted by one or more substituents.An “optionally substituted aryl” refers to an aryl having optionally oneor more substituents (for example 1 to 5 substituents, for example 1, 2,3 or 4) at any available point of attachment. Non-limiting examples ofsuch substituents are selected from halogen, hydroxyl, oxo, nitro,amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl,alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, —SO₂—NH₂, aryl,heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl,alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl,alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl,aminocarbonyl, alkylsulfoxide, —SO₂R^(a), alkylthio, carboxyl, and thelike, wherein R^(a) is alkyl or cycloalkyl.

Where a carbon atom in an aryl group is replaced with a heteroatom, theresultant ring is referred to herein as a heteroaryl ring. The term“heteroaryl” as used herein by itself or as part of another group refersbut is not limited to 5 to 12 carbon-atom aromatic rings or ring systemscontaining 1 to 3 rings which are fused together or linked covalently,typically containing 5 to 8 atoms; at least one of which is aromatic inwhich one or more carbon atoms in one or more of these rings can bereplaced by oxygen, nitrogen or sulfur atoms where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. Such rings may be fused to anaryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examplesof such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl,pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl,thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl,thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl,thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl,tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl,benzofuranyl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl,isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl,benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl,2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl,2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl,2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl,thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl,6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl,6-azaindolyl, 5-azaindolyl, 4-azaindolyl. Within the context of theinstant application the heteroaryls are in particular selected fromfuranyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, indolyl, and isoindolyl.

An “optionally substituted heteroaryl” refers to a heteroaryl havingoptionally one or more substituents (for example 1 to 4 substituents,for example 1, 2, 3 or 4), selected from those defined above forsubstituted aryl, such as for example 1,3-dioxoindolyl.

The term “oxo” as used herein refers to the group ═O.

The term “alkoxy” or “alkyloxy” as used herein refers to a radicalhaving the Formula —OR^(b) wherein R^(b) is alkyl. Preferably, alkoxy isC₁-C₁₀ alkoxy, C₁-C₆ alkoxy, or C₁-C₄ alkoxy. Non-limiting examples ofsuitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Where theoxygen atom in an alkoxy group is substituted with sulfur, the resultantradical is referred to as thioalkoxy. “Haloalkoxy” is an alkoxy groupwherein one or more hydrogen atoms in the alkyl group are substitutedwith halogen. Non-limiting examples of suitable haloalkoxy includefluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy,2,2-difluoroethoxy, 2,2,2-trichloroethoxy; trichloromethoxy,2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy,4,4,4-trichlorobutoxy.

The term “aryloxy” as used herein denotes a group —O-aryl, wherein arylis as defined above.

The term “arylcarbonyl” or “aroyl” as used herein denotes a group—C(O)-aryl, wherein aryl is as defined above.

The term “carboxy” or “carboxyl” or “hydroxycarbonyl” by itself or aspart of another substituent refers to the group —CO₂H. Thus, acarboxyalkyl is an alkyl group as defined above having at least onesubstituent that is —CO₂H.

The term “alkoxycarbonyl” by itself or as part of another substituentrefers to a carboxy group linked to an alkyl radical i.e. to form—C(═O)OR^(e), wherein R^(e) is as defined above for alkyl.

The term “alkylcarbonyloxy” by itself or as part of another substituentrefers to a —O—C(═O)R^(e) wherein R^(e) is as defined above for alkyl.

The term “alkylcarbonylamino” by itself or as part of anothersubstituent refers to an group of Formula —NH(C═O)R or —NR′(C═O)R,wherein R and R′ are each independently alkyl or substituted alkyl.

The term “thiocarbonyl” by itself or as part of another substituentrefers to the group —C(═S)—.

The term “alkoxy” by itself or as part of another substituent refers toa group consisting of an oxygen atom attached to one optionallysubstituted straight or branched alkyl group, cycloalkyl group, aralkyl,or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy groupinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, hexanoxy, and the like.

The term “halo” or “halogen” as a group or part of a group is genericfor fluoro, chloro, bromo, or iodo.

The term “haloalkyl” alone or in combination, refers to an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above. Non-limiting examples of suchhaloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.

The term “haloaryl” alone or in combination, refers to an aryl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above. The term “haloalkoxy” alone orin combination refers to a halo-O-alkyl group wherein the alkyl group issubstituted by 1, 2, or 3 halogen atoms. For example, “haloalkoxy”includes —OCF₃, —OCHF₂, —OCH₂F, —O—CF₂—CF₃, —O—CH₂—CF₃, —O—CH₂—CHF₂, and—O—CH₂—CH₂F.

Whenever the term “substituted” is used in the present invention, it ismeant to indicate that one or more hydrogens on the atom indicated inthe expression using “substituted” is replaced with a selection from theindicated group, provided that the indicated atom's normal valency isnot exceeded, and that the substitution results in a chemically stablecompound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into a therapeutic agent.

Where groups may be optionally substituted, such groups may besubstituted once or more, and preferably once, twice or thrice.Substituents may be selected from, for example, the group comprisinghalogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy,and haloalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each beingoptionally substituted with” or “alkyl, aryl, or cycloalkyl, optionallysubstituted with” refers to optionally substituted alkyl, optionallysubstituted aryl and optionally substituted cycloalkyl.

As described herein, some of the compounds of the invention may containone or more asymmetric carbon atoms that serve as a chiral center, whichmay lead to different optical forms (e.g. enantiomers ordiastereoisomers). The invention comprises all such optical forms in allpossible configurations, as well as mixtures thereof.

More generally, from the above, it will be clear to the skilled personthat the compounds of the invention may exist in the form of differentisomers and/or tautomers, including but not limited to geometricalisomers, conformational isomers, E/Z-isomers, stereochemical isomers(i.e. enantiomers and diastereoisomers) and isomers that correspond tothe presence of the same substituents on different positions of therings present in the compounds of the invention. All such possibleisomers, tautomers and mixtures thereof are included within the scope ofthe invention.

Whenever used in the present invention the term “compounds of theinvention” or a similar term is meant to include the compounds ofgeneral Formula I or II, and any subgroup thereof. This term also refersto the compounds as depicted in Table 1, their derivatives, N-oxides,salts, solvates, hydrates, stereoisomeric forms, racemic mixtures,tautomeric forms, optical isomers, analogues, pro-drugs, esters, andmetabolites, as well as their quaternized nitrogen analogues. TheN-oxide forms of said compounds are meant to comprise compounds whereinone or several nitrogen atoms are oxidized to the so-called N-oxide.

As used in the specification and the appended claims, the singular forms“a”, “an”, and “the” include plural referents unless the context clearlydictates otherwise. By way of example, “a compound” means one compoundor more than one compound.

The terms described above and others used in the specification are wellunderstood to those in the art.

In a further embodiment, the present invention provides compounds offormula I or a stereoisomer, tautomer, racemic, metabolite, pro- orpredrug, salt, hydrate, or solvate thereof,

-   Wherein-   X is selected from N—R₉, O and S;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ taken together with R₄ forms a dioxolane moiety, which is    optionally substituted with from 1 to 3 substituents selected from    —OH, —C₁₋₆alkyl, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl;    -   or R₇ taken together with R₈ forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In a further embodiment, the present invention provides compounds offormula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ taken together with R₄ forms a dioxolane moiety, which is    optionally substituted with from 1 to 3 —C₁₋₆alkyl substituents;-   R₅ represents —H;-   R₆ is selected from —H, —OH, and —O—C₁₋₆alkyl;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅;-   R₈ represents —H; or R₇ taken together with R₈ forms Het₄;-   R₉ is absent;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each    of said —C₁₋₆alkyl is optionally and independently substituted with    from 1 to 3 substituents selected from -halo, and —Ar₁;-   R₁₀, is independently selected from —C₁₋₆alkyl, —Ar₂, and Het₂;    wherein each of said —C₁₋₆alkyl is optionally substituted with from    1 to 3 —Ar₂ substituents;-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl;-   Ar₁, and Ar₂, each independently a 5-10 membered aromatic mono- or    bicycle; wherein each of said Ar₁, and Ar₂ is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, and -phenyl.

In yet a further particular embodiment, the present invention provides acompound according to formula I,

-   Wherein-   X is selected from N—R₉, O and S;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is —OH;-   R₄ is —OH;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl;    -   or R₇ taken together with R₈ forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In a further embodiment, the present invention provides compounds offormula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ and R₄ are —OH;-   R₅ represents —H;-   R₆ is selected from —H, —OH, and —O—C₁₋₆alkyl;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅; in particular R₇    represents —(C═O)—R₁₀;-   R₈ represents —H; or R₇ taken together with R₈ forms Het₄;-   R₉ is absent;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each    of said —C₁₋₆alkyl is optionally and independently substituted with    from 1 to 3 substituents selected from -halo, and —Ar₁;-   R₁₀, is independently selected from —C₁₋₆alkyl, —Ar₂, and Het₂;    wherein each of said —C₁₋₆alkyl is optionally substituted with from    1 to 3 —Ar₂ substituents;-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl;-   Ar₁, and Ar₂, each independently a 5-10 membered aromatic mono- or    bicycle; wherein each of said Ar₁, and Ar₂ is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, and -phenyl.

In a further embodiment, the present invention provides a compoundaccording to formula I,

-   Wherein-   X is selected from N—R₉, O and S;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is absent or selected from —H, —OH, and -halo;-   R₄ is selected from —H, —OH, and -halo;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 substituents selected        from —OH, —C₁₋₆alkyl, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is —H;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl or R₇ taken together with R₈    forms Het₄;-   R₉ is    -   selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and        —Ar₃ when X is N;    -   absent when X is O; or    -   selected from ═O, and —O₂ when X is S;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.

In a further embodiment, the present invention provides compounds offormula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄; in particular R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ and R₄ are —OH; or-   R₅ represents —H;-   R₆ is —H;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅; in particular R₇    represents —(C═O)—R₁₀;-   R₈ represents —H; or R₇ taken together with R₈ forms Het₄;-   R₉ is absent;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each    of said —C₁₋₆alkyl is optionally and independently substituted with    from 1 to 3 substituents selected from -halo, and —Ar₁;-   R₁₀, is independently selected from —C₁₋₆alkyl, —Ar₂, and Het₂;    wherein each of said —C₁₋₆alkyl is optionally substituted with from    1 to 3 —Ar₂ substituents;-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl;-   Ar₁, and Ar₂, each independently a 5-10 membered aromatic mono- or    bicycle; wherein each of said Ar₁, and Ar₂ is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, and -phenyl.

In a further embodiment, the present invention provides compounds offormula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ and R₄ are —OH; or R₃ taken together with R₄ forms a dioxolane    moiety, which is optionally substituted with from 1 to 3 —C₁₋₆alkyl    substituents; in particular R₃ and R₄ are —OH;-   R₅ represents —H;-   R₆ is selected from —H, —OH, and —O—C₁₋₆alkyl; in particular R₆    represents —H;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅; in particular R₇    represents —(C═O)—R₁₀;-   R₈ represents —H;-   R₉ is absent;-   R₁₃, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein said    —C₁₋₆alkyl is optionally substituted with halo or —Ar₁;-   R₁₀, is independently selected from —C₁₋₆alkyl, —Ar₂, and Het₂;    wherein said —C₁₋₆alkyl is optionally substituted —Ar₂; in    particular R₁₀, is independently selected from —Ar₂, and Het₂-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl; in particular R₂₀, and R₂₁ are each independently    —C₁₋₆alkyl;-   Ar₁, and Ar₂, each independently a 5-10 membered aromatic mono- or    bicycle; wherein each of said Ar₁, and Ar₂ is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, and Het₃ are each independently a 5-10 membered mono- or    bicyclic heteroaryl comprising from 1 to 3 heteroatoms selected from    N, O and S; wherein each of said Het₁, Het₂, and Het₃ is optionally    and independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo and -phenyl.

In a further embodiment, the present invention provides compounds offormula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —(C═O)—R₁₃, and —SO₂—R₁₅; wherein    said —C₁₋₆alkyl may be further substituted with —R₂₄;-   R₂ is —H; or R₁ taken together with R₂ forms Het₃;-   R₃ and R₄ are —OH; or R₃ taken together with R₄ forms a dioxolane    moiety, which is optionally substituted with from 1 to 3 —C₁₋₆alkyl    substituents; in particular R₃ and R₄ are —OH;-   R₅ represents —H;-   R₆ is selected from —H, —OH, and —O—C₁₋₆alkyl; in particular R₆    represents —H;-   R₇ is selected from —C₁₋₆alkyl, and —(C═O)—R₁₀; wherein said    —C₁₋₆alkyl may be further substituted with —R₂₅; in particular R₇    represents —(C═O)—R₁₀;-   R₈ represents —H;-   R₉ is absent;-   R₁₃ is selected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, and    —NH—Ar₁; wherein said —C₁₋₆alkyl is optionally substituted with halo    or —Ar₁;-   R₁₅ is selected from —C₁₋₆alkyl, and —Ar₁; wherein said —C₁₋₆alkyl    is optionally substituted with -halo (in particular —F) or Ar₁;-   R₂₄ represents —Ar₁; in particular phenyl;-   R₂₅ represents —Ar₁; in particular phenyl;-   R₁₀, is independently selected from —C₁₋₆alkyl, —Ar₂, and Het₂;    wherein said —C₁₋₆alkyl is optionally substituted —Ar₂; in    particular R₁₀, is independently selected from —Ar₂, and Het₂-   R₂₀, and R₂₁, are each independently selected from —H, and    —C₁₋₆alkyl; in particular R₂₀, and R₂₁ are each independently    —C₁₋₆alkyl; more in particular R₂₀, and R₂₁ are methyl;-   Ar₁, and Ar₂, each independently a 5-10 membered aromatic mono- or    bicycle (in particular phenyl or napthyl); wherein each of said Ar₁,    and Ar₂ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CN, —CF₃, —NR₂₀R₂₁, and -phenyl; in particular Ar₁, and Ar₂,    represent phenyl, wherein each of said phenyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁,    and -phenyl;-   Het₁, Het₂, and Het₃ are each independently selected from pyridinyl,    1,3-dioxoindolyl, indolyl, pyrimidyl, pyridazinyl, pyrazinyl,    pyrazolyl, imidazolyl, furanyl, ‘1,2,3-triazolyl’, and    1H,3H-isoindolyl; wherein each of said Het₁, Het₂, and Het₃ is    optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, halo and -phenyl.

In particular—Het₁, is independently selected from pyridinyl,1,3-dioxoindolyl, indolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrazolyl,and imidazolyl; wherein said Het₁ is optionally and independentlysubstituted with from 1 to 3 substituents selected from ═O, —OH, haloand -phenyl;

-   -   Het₂ is independently selected from 1,3-dioxoindolyl,        pyridazinyl, furanyl, and pyrimidyl; wherein said Het₂, is        optionally and independently substituted with from 1 to 3        substituents selected from ═O, —OH, halo and -phenyl;    -   Het₃, is independently selected from ‘1,2,3-triazolyl’,        1,3-dioxoindolyl, and 1H,3H-isoindolyl; wherein said Het₃ is        optionally and independently substituted with from 1 to 3        substituents selected from ═O, —OH, halo and -phenyl.

In another particular embodiment, the present invention provides acompound of formula I,

-   Wherein-   X is O;-   R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and    —SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₄;-   R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂    forms Het₃;-   R₃ is    -   absent or selected from —H, —OH, and -halo;    -   or R₃ taken together with R₄ forms a dioxolane moiety, which is        optionally substituted with from 1 to 3 substituents selected        from —OH, —C₁₋₆alkyl, and -halo;-   R₄ is selected from —H, —OH, and -halo;-   R₅ is selected from —H, —OH, ═O, and -halo;-   R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, and —CN;-   R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and    —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with    —R₂₅;-   R₈ is selected from —H and —C₁₋₆alkyl or R₇ taken together with R₈    forms Het₄;-   R₉ is absent;-   R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from    —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and    —NH—Ar₁; wherein each of said —C₁₋₆alkyl is optionally and    independently substituted with from 1 to 3 substituents selected    from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,    —C₃₋₆cycloalkyl, -Het₁ and —Ar₁;-   R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,    —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of    said —C₁₋₆alkyl is optionally substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,    —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₃, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂;-   R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently    selected from —H, and —C₁₋₆alkyl;-   Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered    aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄    and Ar₅ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CF₃, or —NR₂₀R₂₁;-   Het₁, Het₂, Het₃ and Het₄ are each independently a 5-10 membered    mono- or bicyclic heteroaryl comprising from 1 to 3 heteroatoms    selected from N, O and S; wherein each of said Het₁, Het₂, Het₃ and    Het₄ is optionally and independently substituted with from 1 to 3    substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,    —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionally    substituted with from 1 to 3 substituents selected from ═O, —OH,    -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CF₃, or —NR₂₂R₂₃.

In a specific aspect, the present invention provides a compound asdefined herein, with its ‘X’ and ‘R’ definitions as defined above,wherein the compound has the stereoisomeric configuration as representedin formula II:

In a further aspect, the R₁ and R₇ substituents of the compounds of thepresent invention are each independently selected to comprise anoptionally substituted polar heteroaryl moiety; in particular selectedfrom the group consisting of pyridyl, pyridazyl, pyrimidyl, pyrazyl and1,3-dioxoindolyl (a.k.a. phthalimide). In this embodiment R₁ ispreferably selected from —C₁₋₆alkyl substituted with —R₂₄, —(C═O)—R₁₃,and —SO₂—R₁₅; wherein said R₂₄, R₁₃ and R₁₅ are defined as in any one ofthe different Het₁ comprising embodiments herein described and whereinsaid Het₁ is selected from the group consisting of pyridyl, pyridazyl,pyrimidyl, pyrazyl and 1,3-dioxoindolyl (a.k.a. phthalimide). In thisembodiment R₇ is preferably selected from —C₁₋₆alkyl substituted with—R₂₅, and —(C═O)—R₁₀; wherein said R₂₅ and R₁₀ are defined as in any oneof the different Het₂ comprising embodiments herein described andwherein said Het₂ is selected from the group consisting of pyridyl,pyridazyl, pyrimidyl, pyrazyl and 1,3-dioxoindolyl (a.k.a. phthalimide).It has been found that such polar heteroaryl analogs have interestingactivities due to their specific interactions with the target.

In another aspect, the R₁ and R₇ substituents of the compounds of thepresent invention are each independently selected to comprise anoptionally substituted phenyl moiety. It has been found that suchbiphenyl analogs have an increased antibiofilm activity. In thisembodiment R₁ is preferably selected from —C₁₋₆alkyl substituted with—R₂₄, —(C═O)—R₁₃, and —SO₂—R₁₅; wherein said R₂₄, R₁₃ and R₁₅ aredefined as in any one of the different Ar₁ comprising embodiments hereindescribed and wherein said Ar₁ is phenyl optionally and independentlysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁, and -phenyl. In thisembodiment R₇ is preferably selected from —C₁₋₆alkyl substituted with—R₂₅, and (C═O)—R₁₀; wherein said R₂₅ and R₁₀ are defined as in any oneof the different Ar₂ comprising embodiments herein described and whereinsaid Ar₂ is phenyl optionally and independently substituted with from 1to 3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁, and -phenyl.

In another aspect the R₁ and R₇ substituents of the compounds of thepresent invention are each independently selected to comprise asubstituted phenyl moiety or a substituted (in particular a polar)heteroaryl moiety, wherein said phenyl moiety or heteroaryl moiety aresubstituted with a substituent selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁, and -phenyl, characterized in thatsaid substituent is present at the ortho position in respect to theattachment point of said phenyl moiety or said heteroaryl moiety withthe rest of the molecule. In a more particular embodiment the R₁substituent of the compounds of the present invention is selected tocomprise a substituted phenyl moiety or a substituted (in particular apolar) heteroaryl moiety, wherein said phenyl moiety or heteroarylmoiety are substituted with a substituent selected from ═O, —OH, -halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁, and -phenyl,characterized in that said substituent is present at the ortho positionin respect to the attachment point of said phenyl moiety or saidheteroaryl moiety with the rest of the molecule. It has been found thatsuch orthosubstitution results in an increased activity.

The compounds of the present invention can be prepared according to thereaction schemes provided in the examples hereinafter, but those skilledin the art will appreciate that these are only illustrative for theinvention and that the compounds of this invention can be prepared byany of several standard synthetic processes commonly used by thoseskilled in the art of organic chemistry.

Medical Use

It is an aim of the present invention to provide compounds thatinterfere with quorum sensing (QS) in bacteria and/or inhibit or preventbiofilm formation.

The present invention thus further provides a pharmaceutical compositioncomprising a compound according to the present invention and apharmaceutically acceptable excipient, diluent and/or carrier.

In a further aspect, the present invention provides a combination, aspart of a composition or in use, of a compound according to the presentinvention with an antimicrobial agent, in particular an antibiotic ordisinfectant. Hence, one or more compounds as described herein and oneor more antimicrobial agents can be part of a single composition or canbe used in a separate or sequential application.

In a specific aspect, the present invention provides a compound,composition or combination according to the present invention, for useas a medicament, more in particular, for use in the prevention,reduction and/or treatment of bacterial infections in humans or animals.In a particular embodiment, said bacterial infection is a Staphylococcusaureus infection.

The compounds of the present invention can be used as an alternative toreplace antibiotics for combating (bacterial) infections or can be usedas an adjunct therapy in combination with e.g. antibiotics so that lowerdoses of the conventional antibiotics are required.

In a particular embodiment, the present invention provides a method ofpreventing, reducing the risk of and/or treating a bacterial infection,more in particular a disorder associated with biofilm formation in asubject; said method comprising administering to a subject in needthereof a therapeutic effective amount of a compound, a composition or acombination according to the present invention. The term “biofilm” asused herein refers to biological films that develop and persist atinterfaces in aqueous environments, on medical implants, or as foci ofchronic infections. Biofilms may also form on biological surfaces suchas teeth, or any other natural or artificial surfaces that may beexposed to or are in contact with non-sterile aqueous environments thatmay include nutrients suitable for the colonization and proliferation ofthe microorganisms. These biological films are composed ofmicroorganisms embedded in organic gelatinous matrices composed of oneor more matrix polymers that are secreted by the residentmicroorganisms. Biofilms can develop into macroscopic structures severalmillimeters or centimeters in thickness and can cover large surfaceareas. Biofilms are also capable of trapping nutrients and particulatesthat can contribute to their enhanced development and stability.Biofilms can also prevent penetration of antimicrobial agents, which maylead to persistent infections. Disorders associated with biofilmformation include but are not limited to, dental caries, periodontitis,otitis media, muscular skeletal infections, necrotizing fasciitis,biliary tract infection, osteomyelitis, bacterial prostatitis,endocarditis, native valve endocarditis, cystic fibrosis pneumonia,meloidosis, or skin lesions associated with bullous impetigo, atopicdermatitis and pemphigus foliaceus or implanted device-relatedinfections. In some embodiments, the disorder is a nosocomial infection,including but not limited to, pneumonia, sepsis (including SIRS(Systemic Inflammatory Response Syndrome), severe sepsis and MODS(multiorgan dysfunction syndrome)), or an infection associated withsutures, exit sites, arteriovenous sites, scleral buckles, contactlenses, urinary catheter cystitis, peritoneal dialysis (CAPD)peritonitis, IUDs, endotracheal tubes, Hickman catheters, central venouscatheters, mechanical heart valves, vascular grafts, biliary stentblockage, and orthopedic devices. The compounds of the present inventionare of particular interest to prevent, limit the risk of and/or treatpost-operative wound infections, skin ulcers, diabetic foot ulcers,pressure ulcers such as decubitus ulcers or bedsores, burn woundinfections, catheter associated infections, and infections resultingfrom animal bites. In a further embodiment, the compounds as describedherein are effective in preventing and/or treating mastitis, i.e.inflammation of the breast tissue. S. aureus is the most commonetiological organism responsible, but S. epidermidis and streptococciare occasionally isolated as well. Mastitis in dairy cattle is thepersistent, inflammatory reaction of the udder tissue.

The present invention further provides a method for the prevention,reducing the risk of and/or treatment of microbial infections, inparticular bacterial infections, more in particular infections withbacteria of the genus Staphylococcus such as Staphylococcus aureusinfections. The method further comprises contacting a surface with thecomposition in an amount sufficient to prevent or reduce the growth orproliferation of microorganisms or biofilm-embedded microorganisms onsaid surface.

In the invention, particular preference is given to compounds of FormulaI or II, or any subgroup thereof, that in the inhibition assay asdescribed in the examples, inhibit with an IC₅₀ value of less than 100μM, preferably less than 50 μM, and more preferably less than 10 μM.

Said inhibition may be effected in vitro and/or in vivo, and wheneffected in vivo, is preferably effected in a selective manner, asdefined above. In some embodiments, the bacterium is contacted with thecompound as provided herein ex vivo. In such an embodiment, for example,the contacting comprises administering the compound to a surface in anamount effective to inhibit biofilm formation on said surface, includingbut not limited to a medical device.

For pharmaceutical use, the compounds of the invention may be used as afree acid or base, and/or in the form of a pharmaceutically acceptableacid-addition and/or base-addition salt (e.g. obtained with non-toxicorganic or inorganic acid or base), in the form of a hydrate, solvateand/or complex, and/or in the form or a pro-drug or pre-drug, such as anester. As used herein and unless otherwise stated, the term “solvate”includes any combination which may be formed by a compound of thisinvention with a suitable inorganic solvent (e.g. hydrates) or organicsolvent, such as but not limited to alcohols, ketones, esters and thelike. Such salts, hydrates, solvates, etc. and the preparation thereofwill be clear to the skilled person; reference is for instance made tothe salts, hydrates, solvates, etc. described in U.S. Pat. Nos.6,372,778, 6,369,086, 6,369,087 and 6,372,733.

The pharmaceutically acceptable salts of the compounds according to theinvention, i.e. in the form of water-, oil-soluble, or dispersibleproducts, include the conventional non-toxic salts or the quaternaryammonium salts which are formed, e.g., from inorganic or organic acidsor bases. Examples of such acid addition salts include acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Base salts include ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. In addition, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethylbromides and others. Other pharmaceutically acceptablesalts include the sulfate salt ethanolate and sulfate salts.

Generally, for pharmaceutical use, the compounds of the invention may beformulated as a pharmaceutical preparation or pharmaceutical compositioncomprising at least one compound of the invention and at least onepharmaceutically acceptable carrier, diluent or excipient and/oradjuvant, and optionally one or more further pharmaceutically activecompounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference isagain made to for instance U.S. Pat. Nos. 6,372,778, 6,369,086,6,369,087 and 6,372,733, as well as to the standard handbooks, such asthe latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, creams,lotions, soft and hard gelatin capsules, suppositories, eye drops,sterile injectable solutions, and sterile packaged powders (which areusually reconstituted prior to use) which may be administered as a bolusand/or for continuous administration, which may be formulated withcarriers, excipients, and diluents that are suitable per se for suchformulations, such as lactose, dextrose, sucrose, sorbitol, mannitol,starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin,calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,polyethylene glycol, cellulose, (sterile) water, methylcellulose,methyl- and propylhydroxybenzoates, talc, magnesium stearate, edibleoils, vegetable oils and mineral oils or suitable mixtures thereof.Furthermore, the compounds may also be formulated in or may be appliedon a medical device, such as skin patches, implantable devices,catheters, tampons, wound dressings and bandages. In a particularembodiment, one or more compounds as described hereinbefore is used toinhibit biofilm formation on a medical device by contacting the devicewith said compound in an amount effective to inhibit biofilm formation.Percutaneous devices (such as catheters) and implanted medical devices(including, but not limited to, pacemakers, vascular grafts, stents, andheart valves) commonly serve as foci for bacterial infection. Thetendency of some microorganisms to adhere to and colonize the surface ofthe device promotes such infections, which increase the morbidity andmortality associated with use of the devices.

For example, one or more compounds of the present invention can be usedor applied on substrates used to manufacture medical devices associatedwith non-invasive and invasive medical procedures. Such substratesinclude, without limitation, tubular, sheet, rod and articles of propershape for use in a number of medical devices such as vascular grafts,aortic grafts, arterial, venous, or vascular tubing, vascular stents,dialysis membranes, tubing or connectors, blood oxygenator tubing ormembranes, surgical instruments, ultrafiltration membranes, intra-aorticballoons, stents, blood bags, catheters, sutures, soft or hard tissueprostheses, synthetic prostheses, prosthetic heart valves, tissueadhesives, cardiac pacemaker leads, artificial organs, endotrachealtubes, lenses for the eye such as contact or intraocular lenses, bloodhandling equipment, apheresis equipment, diagnostic and monitoringcatheters and sensors, biosensors, dental devices, drug deliverysystems, or bodily implants of any kind. In particular, one or morecompounds of the present invention can be used or applied ondrug-eluting medical implants. These are active implants that inducehealing effects in addition to their regular task of support. Thiseffect is achieved by controlled release of the active agent, includingthe compounds of the present invention, into the surrounding tissue.Examples are drug-eluting vascular stents, drug-eluting wound dressingsand protein-eluting scaffolds for tissue regeneration. As such, thepresent invention encompasses a medical device as mentioned hereincomprising one or more compounds of the present invention. The compoundscan be incorporated in or applied on the surface of the medical device.

In a particular embodiment, the composition or formulation of thepresent invention can optionally contain other pharmaceutically activesubstances, especially antimicrobial agents such as antibiotics ordisinfectants (which may or may not lead to a synergistic effect withthe compounds of the invention) and/or other substances that arecommonly used in pharmaceutical formulations, such as lubricatingagents, wetting agents, emulsifying and suspending agents, dispersingagents, disintegrants, bulking agents, fillers, preserving agents,sweetening agents, flavoring agents, flow regulators, release agents,etc.

In some embodiments, the method and use as described herein furthercomprises the step of administering a standard of care antimicrobialagent to the subject. “Standard of care” as used herein refers to atreatment that is generally accepted by clinicians for a certain type ofpatient diagnosed with a type of illness. Exemplary standard of careantimicrobial agents include, but are not limited to, (i) β-lactamantibiotics like penicillins either alone (including but not limited topenicillin G, penicillin V, flucloxacillin, oxacillin, ampicillin,methicillin, amoxicillin, temocillin, and piperacillin), or combinedwith a β-lactamase inhibitors (including but not limited toamoxicillin+clavulanic acid, and piperacillin+tazobactam), carbapenems(including but not limited to biapenem, meropenem and imipenem),monobactams (including but not limited to aztreonam) and cephalosporins(including but not limited to cefadroxil, cefalexine, cefazoline,cefuroxime, cefotaxim, ceftazidim, ceftriaxone, cefepim and ceftarolin),(ii) macrolides (including but not limited to erythromycin,azithromycin, clarithromycin, roxithromycin, and spiramycin), (iii)tetracyclines and glycycicyclines (including but not limited todoxycycline, lymecycline, minocycline, and tigecycline), (iv)lincosamides (including but not limited to clindamycin and lincomycin),(v) (fluoro-)quinolones (including but not limited to ciprofloxacin,levofloxacin, nemonoxacin, garenoxacin, moxifloxacin, norfloxacin,ofloxacin, parfloxacin, gemifloxacin, zabofloxacin and cinafloxacin),(vi) trimethoprim+sulfamethoxazole, (vii) aminoglycosides (including butnot limited to streptomycin, amikacin, gentamicin, paromomycin,kanamycin, spectinomycin and tobramycin), (viii) glycopeptides(including but not limited to oritavancin, LY-333328, dalbavancin,teicoplanin and vancomycin), (ix) polymyxins (including but not limitedto polymyxin B and colistin), (x) anti-tuberculosis drugs (including butnot limited to isoniazide, rifampicin, pyrazinamide, ethambutol andbedaquilin and p-aminosalicylic acid), (xi) oxazolidinones (includingbut not limited to tedizolid, AZD-2563 and linezolid), (xii)lipopeptides (including but not limited to daptomycin and ramoplanin),(xiii) streptogramins (including but not limited toquinupristin/dalfopristin, pristinamycin, virginiamycin and NXL-103),(xiv) ketolides (including but not limited to telithromycin andsolithromycin), (xv) various other antibiotics, including but notlimited to cycloserine, fosfomycin, nitrofurantoin, nifurtoinol,thiamphenicol, chloramphenicol, metronidazole, bacitracin and mupirocin,and (xvi) locally applied disinfectants including but not limited tochlorhexidine, PVP-I₂ (Povidone-iodine), colloidal silver, Manuka honey,ozonated olive oil, silver nitrate, silver sulfadiazine, ethanol,isopropanol, hydrogen peroxide, chloroxylenol, and cetrimide,benzalkoniumchloride and other quaternary ammonium compounds.

Combination therapy comprising a compound of the present invention andan antimicrobial agent, e.g. an antibiotic or disinfectant, describedherein for the treatment of a bacterial infection is specificallycontemplated. For example, in one embodiment, the invention provides amethod of treating a bacterial infection or a disorder associated withbacterial QS and/or biofilm formation in a subject comprisingadministering to the subject a therapeutically-effective amount of acombination therapy comprising (a) a compound of formula I or II or anysubgroup thereof, and (b) an antimicrobial agent.

Such combination therapy would be provided in a combined amounteffective to prevent or inhibit QS and/or biofilm formation of thebacteria and/or prevent or treat the bacterial infection and/or treatthe disorder associated with biofilm formation. This process involvesadministering to a subject in need thereof the compound and a (standardof care) therapeutic agent at the same time, which may be achieved byadministering a single composition or pharmacological formulation thatincludes both the compound of the invention and a therapeutic agent, orby administering two distinct compositions or formulations, at the sametime, wherein one composition includes the compound of the invention andthe other includes a (standard of care) therapeutic agent. In anotherembodiment, the combination therapy involves administering to a subjectin need thereof the compound of the invention and a (standard of care)therapeutic agent at different times, which may be achieved byadministering two distinct compositions or formulations, at differenttime intervals, wherein one composition includes the compound of theinvention and the other includes a (standard of care) therapeutic agent.

The compositions may also be formulated so as to provide rapid,sustained or delayed release of the active compound(s) containedtherein, for example using liposomes or hydrophilic polymeric matricesbased on natural gels or synthetic polymers. In order to enhance thesolubility and/or the stability of the compounds of a pharmaceuticalcomposition according to the invention, it can be advantageous to employα-, β- or γ-cyclodextrins or their derivatives. An interesting way offormulating the compounds in combination with a cyclodextrin or aderivative thereof has been described in EP-A-721,331. In particular,the present invention encompasses a pharmaceutical compositioncomprising an effective amount of a compound according to the inventionwith a pharmaceutically acceptable cyclodextrin.

In addition, co-solvents such as alcohols may improve the solubilityand/or the stability of the compounds. In the preparation of aqueouscompositions, addition of salts of the compounds of the invention can bemore suitable due to their increased water solubility.

Particular reference is made to the compositions, formulations (andcarriers, excipients, diluents, etc. for use therein), routes ofadministration etc., which are known per se for analogouspyridinocarboxamides, such as those described in U.S. Pat. No. 4,997,834and EP-A-0 370 498.

More in particular, the compositions may be formulated in apharmaceutical formulation comprising a therapeutically effective amountof particles consisting of a solid dispersion of the compounds of theinvention and one or more pharmaceutically acceptable water-solublepolymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

It may further be convenient to formulate the compounds in the form ofnanoparticles which have a surface modifier adsorbed on the surfacethereof in an amount sufficient to maintain an effective averageparticle size of less than 1000 nm. Suitable surface modifiers canpreferably be selected from known organic and inorganic pharmaceuticalexcipients. Such excipients include various polymers, low molecularweight oligomers, natural products and surfactants. Preferred surfacemodifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according tothe invention involves a pharmaceutical composition whereby thecompounds are incorporated in hydrophilic polymers and applying thismixture as a coat film over many small beads, thus yielding acomposition with good bio-availability which can conveniently bemanufactured and which is suitable for preparing pharmaceutical dosageforms for oral administration. Materials suitable for use as cores inthe beads are manifold, provided that said materials arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, and saccharides and derivatives thereof. Thepreparations may be prepared in a manner known per se, which usuallyinvolves mixing at least one compound according to the invention withthe one or more pharmaceutically acceptable carriers, and, if desired,in combination with other pharmaceutical active compounds, whennecessary under aseptic conditions. Reference is again made to U.S. Pat.Nos. 6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the further priorart mentioned above, as well as to the standard handbooks, such as thelatest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 1 and 1000 mg, and usually between 5 and 500 mg, ofthe at least one compound of the invention, e.g. about 10, 25, 50, 100,200, 300 or 400 mg per unit dosage.

The compounds can be administered by a variety of routes including theoral, rectal, ocular, transdermal, subcutaneous, intravenous,intramuscular or intranasal routes, depending mainly on the specificpreparation used and the condition to be treated or prevented, and withoral and intravenous administration usually being preferred. At leastone compound of the invention will generally be administered in an“effective amount”, by which is meant any amount of a compound of theFormula I or II or any subgroup thereof that, upon suitableadministration, is sufficient to achieve the desired therapeutic orprophylactic effect in the individual to which it is administered. Morespecific, it refers to an amount of the compound at least sufficient toachieve a desired modulation of the activity or physiological propertyof a microbial population as exemplified in the present examples. Theeffective amount is determined, at least in part, upon the compoundused, the microbial species present, the structure, system, or host, andthe desired level of regulation. Modulating the activity orphysiological property of the microbial population includes, but is notlimited to, slowing, attenuating, inhibiting, or enhancing thecolonization of a surface or proliferation of bacteria, inhibiting theformation of a biofilm, and the like. Modulation includes slowing theformation of bacteria or new bacteria if some bacteria are alreadypresent, inhibiting the formation of a biofilm. Usually, depending onthe condition to be prevented or treated and the route ofadministration, such an effective amount will usually be between 0.01 to1000 mg per kilogram body weight day of the patient per day, more oftenbetween 0.1 and 500 mg, such as between 1 and 250 mg, for example about5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day ofthe patient per day, which may be administered as a single daily dose,divided over one or more daily doses, or essentially continuously, e.g.using a drip infusion. The amount(s) to be administered, the route ofadministration and the further treatment regimen may be determined bythe treating clinician, depending on factors such as the age, gender andgeneral condition of the patient and the nature and severity of thedisease/symptoms to be treated. Reference is again made to U.S. Pat.Nos. 6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the further priorart mentioned above, as well as to the standard handbooks, such as thelatest edition of Remington's Pharmaceutical Sciences.

In accordance with the method of the present invention, saidpharmaceutical composition can be administered separately at differenttimes during the course of therapy or concurrently in divided or singlecombination forms. The present invention is therefore to be understoodas embracing all such regimes of simultaneous or alternating treatmentand the term “administering” is to be interpreted accordingly.

For an oral administration form, the compositions of the presentinvention can be mixed with suitable additives, such as excipients,stabilizers, or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case, the preparation can be carriedout both as dry and as moist granules. Suitable oily excipients orsolvents are vegetable or animal oils, such as sunflower oil or codliver oil. Suitable solvents for aqueous or alcoholic solutions arewater, ethanol, sugar solutions, or mixtures thereof. Polyethyleneglycols and polypropylene glycols are also useful as further auxiliariesfor other administration forms. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents and lubricantsknown in the art.

When administered by nasal aerosol or inhalation, these compositions maybe prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. Suitablepharmaceutical formulations for administration in the form of aerosolsor sprays are, for example, solutions, suspensions or emulsions of thecompounds of the invention or their physiologically tolerable salts in apharmaceutically acceptable solvent, such as ethanol or water, or amixture of such solvents. If required, the formulation can alsoadditionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous administration, the compound according to theinvention, if desired with the substances customary therefore such assolubilizers, emulsifiers or further auxiliaries are brought intosolution, suspension, or emulsion. The compounds of the invention canalso be lyophilized and the lyophilizates obtained used, for example,for the production of injection or infusion preparations. Suitablesolvents are, for example, water, physiological saline solution oralcohols, e.g. ethanol, propanol, glycerol, in addition also sugarsolutions such as glucose or mannitol solutions, or alternativelymixtures of the various solvents mentioned. The injectable solutions orsuspensions may be formulated according to known art, using suitablenon-toxic, parenterally-acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodiumchloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, theseformulations may be prepared by mixing the compounds according to theinvention with a suitable non-irritating excipient, such as cocoabutter, synthetic glyceride esters or polyethylene glycols, which aresolid at ordinary temperatures, but liquefy and/or dissolve in therectal cavity to release the drug. In preferred embodiments, thecompounds and compositions of the invention are used locally, forinstance topical or in both absorbed and non-adsorbed applications.

In a particular embodiment, compositions comprising a compound of thepresent invention, either alone or in combination as described herein,can be used as a topical agent. The topical agent is a solution, thatis, in one aspect, a liquid formulation comprising the compound and acarrier. Other suitable forms include semi-solid or solid formscomprising a carrier indigenous to topical application and having adynamic viscosity preferably greater than that of water, provided thatthe carrier does not deleteriously react with the compound in thecomposition. Suitable formulations include, but are not limited to, lipbalms, suspensions, emulsions, creams, ointments, powders, liniments,salves and the like. If desired, these compositions may be sterilized ormixed with auxiliary agents, including but not limited to,preservatives, stabilizers, wetting agents, buffers or salts forinfluencing osmotic pressure and the like well known in the art.Preferred vehicles for semi-solid or solid forms topical preparationsinclude ointment bases, conventional ophthalmic vehicles; creams; andgels. These topical preparations optionally contain emollients,perfumes, and/or pigments to enhance their acceptability for varioususages, provided that the additives do not deleteriously react with thecompound in the composition.

Also suitable for topical application are sprayable aerosol preparationswherein the compound, preferably in combination with a solid or liquidinert carrier material, is packaged in a squeeze bottle or in admixturewith a pressurized volatile, normally gaseous propellant, e.g., a Freon(chlorofluorocarbon) or environmentally acceptable volatile propellant.Such compositions are used in one aspect, for application to the skin orto mucous membranes. The aerosol or spray preparations optionallycontain solvents, buffers, surfactants, perfumes, and/or antioxidants inaddition to the compound.

The compositions of the present invention are further of value in theveterinary field, which for the purposes herein not only includes theprevention and/or treatment of diseases in animals, but also—foreconomically important animals such as cattle, pigs, sheep, chicken,fish, etc.—enhancing the growth and/or weight of the animal and/or theamount and/or the quality of the meat or other products obtained fromthe animal. Thus, in a further aspect, the invention relates to acomposition for veterinary use that contains at least one compound ofthe invention and at least one suitable carrier (i.e. a carrier suitablefor veterinary use). The invention also relates to the use of a compoundof the invention in the preparation of such a composition.

As used herein, the term “subject” includes humans, mammals (e.g., cats,dogs, horses, chicken, pigs, hogs, cows, fish, crabs, shrimps, cattle,and other), and other living species that are in need of treatment. Inparticular, the term “host” includes humans.

In related variations of the preceding embodiments, a compositioncomprising a compound of the present invention packaged alone, e.g., ina kit or package or unit dose, or is optionally arranged to permitco-administration with one or more other (therapeutic) agents asdescribed herein, but the compound and the agent are not in admixture.In an alternative variation, the compound and the agent are inadmixture. In some embodiments, the two components to the kit/unit doseare packaged with instructions for administering the two agents to ahuman subject for treatment of one of the above-indicated disorders anddiseases. The kit may comprise a composition described herein incombination with a vehicle in a cream or gel base, as a pump-spray, asan aerosol, on an impregnated bandage, or in a dropper.

This invention will be better understood by reference to theexperimental details that follow, but those skilled in the art willreadily appreciate that these are only illustrative of the invention asdescribed more fully in the claims that follow thereafter. Particularembodiments and examples are not in any way intended to limit the scopeof the invention as claimed. Additionally, throughout this application,various publications are cited. The disclosure of these publications ishereby incorporated by reference into this application to describe morefully the state of the art to which this invention pertains.

EXAMPLES

Compound Synthesis—Reaction Schemes

The compounds of the invention may be prepared by methods well known tothose skilled in the art, and as described in the synthetic andexperimental procedures shown below.

Hamamelitannin (HAM) has been identified as an antimicrobialpotentiator, capable of increasing the susceptibility of S. aureus toexisting antibiotics. To gain insight into the structure-activityrelationship of HAM, as well as to discover analogues with enhancedpotency, better drug-like properties and metabolic stability, we set outto synthesize structural analogues of hamamelitannin as to:

-   -   explore the importance of the aromatic hydroxyl groups.    -   replace the metabolically unstable ester groups in HAM with        isosteric linker moieties.    -   replace the central sugar moiety by a polysubstituted        tetrahydrofuran ring.

With reference to the specific compounds of the present invention, thefollowing reaction schemes and procedures may be used.

Scheme 1 describes the synthesis of a series of amide analogues of HAM(15-21). The desired compounds are synthesized fromisopropylidene-D-ribonolactone. A key step is the aldol condensation of2 with formaldehyde to afford the 2-C-hydroxymethyl derivative 3 (Simoneet al., 2008). Bisazide scaffold 7, readily available from the branchedazidolactole 3 via selective protection and deprotection of functionalgroups, functions as a precursor to generate a series of amidederivatives of HAM.

The central D-hamamelose scaffold is a monosaccharide with anomerichydroxyl function. To assess the importance of the anomeric hydroxylgroup, we synthesized analogues with a cyclic ether (tetrahydrofuran)scaffold. The synthetic strategy to remove the anomeric OH (with theformation of a cyclic ether) is shown in Scheme 2 (Bouisset et al.,2008; Taki et al., 2008). A key step is the tosylate-promotedcyclisation of ribitol 22. The rigidity of the dioxolane ring systemensures that only the cis-bicylic compound 23 is formed. Tetrahydrofuranderivative 24 acts as a versatile orthogonally protected intermediateand gives access to different analogues with different amide groups, asexemplified in Scheme 2 and Scheme 6. Strong acid conditions allowremoval of the acetonide to produce the final compounds (Scheme 8).

In addition to the amide derivatives described earlier, analogues withalternative linkers may be synthesized (Boren et al., 2008;Garcia-Moreno et al., 2000). Intermediate 26 serves to constructanalogues with alternative linkers, as exemplified in Scheme 3:regioisomers 105 and 106 are synthesized via a copper- orruthenium-catalyzed 1,3-dipolar cycloaddition reaction, respectively.Intermediate 33, readily available from 26 via Staudinger reduction, maygive rise to sulfonamides 94-103). The 2-bromobenzenesulfonamide 103serves as an intermediate that is used in the synthesis of biphenylanalogue 104 via a Suzuki cross-coupling (Scheme 4). The library isfurther extended with urea and thiourea derivatives 107 and 108 alongwith the amide derivatives 109 and 110. Benzylamine 112 is obtained viareductive amination of 33 with benzaldehyde. To obtain the finalcompounds, the 1,3-dioxolane is cleaved by treatment with aqueoustrifluoroacetic acid (Scheme 8). Radical bromination of methyl2-methylbenzoate and subsequent treatment with amine 33 afforded cyclicamide derivative 114 (Scheme 5).

Monoalkylation of the amide group in 2′-position was achieved viaalkylation of intermediate 26 (Scheme 2). Intermediate 117 was subjectedto a diazo transfer with freshly prepared TfN₃. Resulting azide 148allowed monoalkylation on the 5-position of the molecule (Scheme 7).

Compound 264 differs from HAM in that the ester linkers are replaced bythe metabolically more stable amides and the central sugar moiety isreplaced by the cyclic ether structure that gives a more rigidpharmacophore. Scheme 9 shows how this derivative with two identicalgalloyl groups is synthesized.

In order to investigate the stereochemical requirements at C-4, compound270 was synthesized. The synthesis starts from2,3-O-isopropylidene-D-ribonolactone (Scheme 10). After mesylation, thislactone was subjected to alkaline treatment with aqueous KOH. Finally,trituration in acetone gave rise to epimer 265 (Batra et al., 2006). C-4inversion occurs via an intermediate epoxide that is openedintramolecularly in a 5-exo-tet process.

Compound 265 was converted to the 2-C-branched-chain derivative 267according to the method of Simone. Borohydride reduction,tosylate-promoted cyclisation and subsequent substitution with sodiumazide gave intermediate 269. Reduction of this bis-azide scaffold withtrimethylphosphine, coupling with benzoic acid and removal of theacetonide protecting group gave the desired 4-epimer.

Compound Synthesis—Experimental Methods

General Procedure 1: Synthesis of Protected Homodibenzamides 8-14 fromBisazide 7.

To a solution of bisazide 7 in THF (0.2 M) was added Me₃P (1M in THF, 10eq.) and the mixture was stirred for 2 h at rt. Water (100 μL per mmolbisazide) was added and stirring was continued for 15 minutes. Themixture was taken to dryness and co-evaporated twice with toluene. Thecrude bisamine was taken up in DMF (to a concentration of 0.1 M).EDC.HCl (3.0 eq.), DMAP (1.0 eq.) HOBt (1.0 eq.) and the appropriatecarboxylic acid (2.5 eq.) were added and the mixture was stirredovernight. The mixture was taken to dryness, the residue was redissolvedin EtOAc, transferred to a separatory funnel and washed successivelywith HCl (1M, twice) and NaHCO₃ (sat. aq., twice). The organic layer wasdried (Na₂SO₄) and concentrated in vacuo. The residue was purified bysilica gel chromatography (CH₂Cl₂/MeOH system) to yield thehomobisbenzamide as a pale yellow foam (yields 85-95%).

General Procedure 2: Full Deprotection of the HomobisbenzamideDerivatives 8-14 to Compounds 15-21.

A solution of bisbenzamide (8-14) (0.05 M) in HOAc was placed under a N₂atmosphere. Palladium black (20 mg/mmol bisbenzamide) was added and thereaction vessel was purged again with N₂. Hydrogen gas was bubbledthrough the solution for 5 h until all benzylethers were cleaved (MSanalysis). The vessel was purged with nitrogen gas and the reactionmixture was filtered over a Whatman fiberglass filter. The filtrate wasconcentrated in vacuo, the residue redissolved in TFA (35% aq. solution)and stirred for 3 h. The solution was concentrated and the residue wasdissolved in a mixture of water and tBuOH (4:1 v/v). The mixture wasfrozen and lyophilized overnight yielding the product as an off whiteamorphous solid (yields 90%-quant.).

General Procedure 3: Staudinger Reduction

A solution of compounds 26-32 or azide 149 (0.4 to 0.6 mmol) in THF (10mL/mmol) was treated with Me₃P (1 M solution, 5 eq.) and the reactionmixture was stirred for 3 h. Water (13 eq.) was added and the solutionwas stirred for another hour, after which it was concentrated. Theresidue was co-evaporated with toluene. The obtained crude amine wasused without further purification.

General Procedure 4: EDC-mediated Amide Formation.

To a solution of amine 25, crude amine 33, the crude amines obtainedafter reduction of azides 27-32, amines 117-118, or the crude aminesobtained after reduction of azide 149 in DMF (25 mL/mmol) were added theappropriate organic acid (1.5 eq.), EDC.HCl (2 eq.),diisopropylethylamine (4 eq.) and a catalytic amount of1-hydroxybenzotriazole and the reaction mixture was stirred overnight atrt. The reaction mixture was concentrated and partioned between waterand EtOAc. The organic layer was dried over sodium sulphate, filteredand evaporated. The products were then purified by column chromatographywith appropriate eluents.

General Procedure 5: Formation of 5-sulfonamide Derivatives 94-103 fromAmine 33.

A solution of the crude amine 33 in CH₂Cl₂ (20 mL/mmol) was cooled in anice-bath, treated with triethylamine (2 eq.) and the appropriatesulfonyl chloride (1 eq.) and the reaction mixture was stirred for 3 h.When TLC indicated that the reaction was finished, the reaction mixturewas concentrated under reduced pressure. The residue was taken up inEtOAc and washed with 0.1 M aq. HCl and sat. aq. NaHCO₃ solution. Theorganic layer was dried over sodium sulphate, filtered and concentrated.The residue was purified by column chromatography.

General Procedure 6: One-pot Staudinger Reduction and Amide Formationfrom Phthalimide 24.

To a solution of phthalimide 24 in THF (10 mL/mmol) was added theappropriate acid chloride (2 eq.), followed by PMe₃ (1M solution in THF,4 eq). Floculation was observed upon addition, after which the reactionmixture turned yellow. The RM was stirred overnight at rt. TLC analysis(toluene/EtOAc 1:1) showed complete consumption of starting material.The RM was concentrated in vacuo and adsorbed onto celite. Purificationvia FCC (toluene/EtOAc 1:0→1:1) afforded compounds 115 and 116.

General Procedure 7: Ing-Manske Procedure for Cleavage of Phthalimides115 and 116

To a solution of phthalimides 115-116 in EtOH (12 to 20 mL/mmol) wasadded hydrazine monohydrate (2 eq.). The RM was heated to 60° C. for 5h. When the reaction was complete (TLC toluene/EtOAc 1:1 and CH₂Cl₂/MeOH9:1), the RM was concentrated in vacuo and the residue adsorbed ontocelite. Purification via FCC (CH₂Cl₂/MeOH/NH₄OH 100:0:1→85:15:1)afforded compounds 117 and 118.

General Procedure 8: Deprotection—Cleavage of Acetonide.

A known amount of the isopropylidene protected compound was treated witha 35% aq. CF₃COOH solution (30 mL/mmol) overnight at room temperature.For the more lipophilic derivatives the reaction mixture was put atultra sound for 2-3 h. When TLC indicated that the deprotection wascomplete, the reaction mixture was concentrated and, if required,purified by column chromatography.

(3aR,6R,6aR)-6-(Azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one(1)

To a solution of 2,3-O-isopropylidene-D-ribonolactone (15.1 g, 80.0mmol) and triethylamine (22.3 mL, 160.0 mmol) in CH₂Cl₂ (400 mL) stirredat 0° C., methanesulfonyl chloride (7.4 mL, 96.0 mmol) was addeddropwise under nitrogen atmosphere. The reaction mixture was allowed toattain ambient temperature. After 3 hours, TLC analysis (toluene/EtOAc3:2) showed complete consumption of the starting material. The reactionmixture was washed with saturated sodium bicarbonate solution and water.The organic layer was dried over sodium sulphate, filtered andconcentrated in vacuo to afford the mesylate as a yellow to orangecolored oil. To this crude mesylate, dissolved in DMF (400 mL), wasadded sodium azide (26.0 g, 400.0 mmol). After overnight reaction at 60°C., TLC analysis (toluene/EtOAc 3:2) showed the presence of one majorproduct. The solvent was evaporated and the residue was taken up inEtOAc (350 mL). The resulting solution was washed with saturated sodiumbicarbonate solution and water. The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo. This crude material waspurified by flash column chromatography (toluene/EtOAc 3:2) to affordazidolactone 1 as a pale yellow oil (93.9% over two steps). ¹H NMR (300MHz, CDCl₃) δ ppm 1.38 (s, 3 H) 1.47 (s, 3 H) 3.67 (dd, J=13.2, 2.3 Hz,1 H) 3.79 (dd, J=13.2, 3.2 Hz, 1 H) 4.64 (app. d, J=5.9 Hz, 1 H) 4.67(app. t, J=2.8 Hz, 1 H) 4.85 (d, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃)δ ppm 25.6, 26.8, 52.7, 75.3, 78.2, 80.2, 113.8, 173.5.

(3aR,6R,6aR)-6-(Azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(2)

Azidolactone 1 (13.9 g, 65.3 mmol) was dissolved in CH₂Cl₂ (170 mL) andcooled to −78° C. This solution was flushed with nitrogen gas, afterwhich a solution of diisobutylaluminium hydride (1M in toluene, 71.8 mL,71.8 mmol) was added dropwise. The cooled solution was allowed to reactfor 4 hours under nitrogen. The reaction was quenched by adding EtOAc(11 mL) and the mixture was allowed to come to room temperature over 30min, after which a saturated Na⁺/K⁺ tartrate solution (450 mL) wasadded. The mixture was stirred for another hour and extracted with EtOAc(4×250 mL). The combined organic layers were dried (sodium sulphate),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (hexane/EtOAc 3:1) to afford 13.7 g ofazidolactole 2 as a pale oil (97.5%). Anomeric ratio=82:18. Majoranomer: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.33 (s, 3 H) 1.49 (s, 3 H) 3.39(dd, J=12.6, 5.9 Hz, 1 H) 3.57 (dd, J=12.6, 7.3 Hz, 1 H) 4.05 (d, J=4.4Hz, 1 H) 4.32 (ddd, J=7.3, 5.9, 0.9 Hz, 1 H) 4.61-4.72 (m, 2 H) 5.47 (d,J=4.7 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 24.9, 26.4, 54.0, 82.2,85.5, 86.0, 103.3, 112.8.

(3aR,6R,6aR)-6-(Azidomethyl)-3a-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(3)

To a stirred solution of 2 (13.7 g, 63.7 mmol) in MeOH (400 mL) wasadded K₂CO₃ (4.4 g, 31.8 mmol) and an aqueous solution of formaldehyde(38% aqueous solution, 130 mL). The solution was heated under reflux.After 24 h, TLC analysis (CH₂Cl₂/MeOH 97:3) showed complete consumptionof the starting material and the presence of a major product. Thereaction mixture was cooled to ambient temperature and the MeOH wasevaporated under reduced pressure. The residual aqueous solution wasextracted with EtOAc (3×250 mL). The organic layers were combined, driedover sodium sulphate, filtered and concentrated. The residue waspurified by flash chromatography (CH₂Cl₂/MeOH 98:2) to afford compound 3as a colorless syrup in 83.5% yield, along with a significant amount oftriol 22 (11.5%). Anomeric ratio=56:44. Major anomer: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.43 (s, 3 H) 1.50 (s, 3 H) 2.64 (t, J=6.9 Hz, 1 H) 3.37(dd, J=12.6, 5.9 Hz, 1 H) 3.60 (dd, J=12.6, 7.9 Hz, 1 H) 3.74-3.98 (m, 3H) 4.28-4.36 (m, 1 H) 4.52 (app. s, 1 H) 5.49 (d, J=4.4 Hz, 1 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.7, 28.1, 53.6, 63.41, 84.8, 85.5, 91.6,105.2, 114.1. Minor anomer: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s, 3 H)1.60 (s, 3 H) 2.17 (t, J=5.7 Hz, 1 H) 3.46 (dd, J=12.9, 4.7 Hz, 1 H)3.53 (dd, J=13.0, 4.5 Hz, 1 H) 3.74-3.98 (m, 3 H) 4.28-4.36 (m, 1 H)4.53 (d, J=0.9 Hz, 1 H) 5.22 (d, J=8.5 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃)δ ppm 27.3, 27.4, 52.6, 63.35, 80.8, 83.7, 93.7, 98.2, 115.5.

(3aR,6R,6aR)-6-(Azidomethyl)-3a-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol (4)

5-Azido-5-deoxy-2,3-O-isopropylidene-D-hamamelose (5.6 g, 22.8 mmol) wastaken up in DMF (250 mL). The solution was placed under a nitrogenatmosphere and cooled to 0° C. Imidazole (2.4 g, 35 mmol) andtert-butylchlorodimethylsilane (4.1 g, 27 mmol) were added and themixture was stirred for 16 h allowing the temperature to rise to rt. Themixture was taken to dryness and the residue was redissolved in EtOAc(200 mL) and water (200 mL) and transferred to a separatory funnel. Thelayers were separated and the aqueous layer was extracted with ethylacetate (3×100 mL). All organic fractions were pooled, dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (toluene/EtOAc 95:5) yielding the title product 4(5.2 g, 14.5 mmol, 63.4%) as a colorless oil alongside significantamounts of starting material, anomeric- and bis-silylether. Theabovementioned side products could be recycled into the startingmaterial via a TBAF mediated deprotection. Anomeric ratio=29:71. Majoranomer: ¹H NMR (300 MHz, CDCl₃) δ ppm 0.07 (s, 6 H), 0.90 (m, 9 H), 1.42(s, 3 H), 1.53 (s, 3 H), 3.30-3.42 (m, 2 H) 3.72 (dd J=12.8 Hz, J=10.5Hz, 2H), 3.80 (d, J=9.7 Hz 1 H) 3.90-3.95 (m, 1 H) 4.17-4.24 (m, 1 H),4.51 (d, J=1.93 Hz, 1 H) 5.11 (d, J=9.7 Hz, 1 H). ¹³C NMR (75 MHz,CDCl₃) d ppm −5.6, −5.4, 18.3, 25.9, 27.9, 28.0, 53.4, 63.6, 84.4, 84.6,93.20, 105.5, 114.0. Minor anomer: ¹H NMR (300 MHz, CDCl₃) δ ppm 0.08(s, 3 H) 0.09 (s, 3 H) 0.89 (s, 9 H) 1.38 (s, 3 H), 1.44 (s, 3 H), 3.29(dd J=11.8 Hz, J=6.8 Hz, 1H) 3.53 (dd J=11.8 Hz, J=6.8 Hz 1 H) 3.79 (d,J=10.9 Hz, 1 H) 3.93 d, J=10.9 Hz, 1 H) 4.17-4.24 (m, 1 H) 4.32 (d,J=6.32 Hz, 1 H) 4.48 (d, J=1.40 Hz, 1 H), 5.34 (d, J=6.32 Hz, 1 H). ¹³CNMR (75 MHz, CDCl₃) d ppm −5.6, −5.5, 18.4, 25.9, 27.3, 27.4, 51.7,63.2, 80.5, 83.7, 90.8, 97.8, 114.3, 114.9. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₅H₃₀N₃O₅Si⁺ 360.19492; Found 360.1953.

((3aR,4R,6R,6aR)-6-(Azidomethyl)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methanoland((3aR,4S,6R,6aR)-6-(Azidomethyl)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methanol(5)

Silylether 4 (14.5 g, 40 mmol) was taken up in DMF (400 mL) and benzylbromide (5.3 mL, 7.5 g, 44 mmol) was added. The reaction mixture wasplaced under a N₂ atmosphere and cooled to 0° C. on ice. Sodium hydride(60% in mineral oil, 2.0 g, 50 mmol) was added in portions. The mixturewas stirred overnight allowing the temperature to rise to rt. MeOH (5mL) was added and stirring was continued for 1 h. The reaction mixturewas poured into a separatory funnel containing water (1.0 L) and theresulting liquid has extracted with diethylether (4×300 mL). All organicextracts were pooled, dried (Na₂SO₄) and taken to dryness. The crudeintermediate was dissolved in THF (300 mL) and TBAF (50 mL 1.0 M in THF,50 mmol) was added. After 4 h the reaction mixture was concentrated invacuo and the residue was redissolved in EtOAc (400 mL) and water (400mL). The biphasic mixture was transferred to a separatory funnel andseparated. The aqueous phase was extracted with ethyl acetate (2×250mL). All organic fractions were pooled, dried (Na₂SO₄) and taken todryness. The residue was purified by silica gel chromatography to yielda higher running (5.7 g, 17.0 mmol, 42.5%) and a lower running anomer(5.6 g, 16.7 mmol, 41.8%) both as colorless oils. Top anomer: ¹H NMR(300 MHz, CDCl₃) δ ppm 1.40 (s, 3 H) 1.48 (s, 3 H) 2.58 (br. s., 1 H)3.27 (dd, J=12.6, 6.4 Hz, 1 H) 3.48 (dd, J=12.6, 8.4 Hz, 1 H) 3.77 (d,J=12.2 Hz, 1 H) 3.89 (d, J=12.2 Hz, 1 H) 4.33 (ddd, J=8.4, 6.4, 1.10 Hz,1 H) 4.46-4.56 (m, 2 H) 4.80 (d, J=11.6 Hz, 1 H) 5.20 (s, 1 H) 7.23-7.39(m, 5 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 28.0, 53.4, 62.9, 70.2,84.7, 85.6, 93.7, 109.5, 113.8, 127.9, 128.1, 128.6, 136.6. Bottomanomer: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (s, 3 H) 1.54 (s, 3 H) 2.80(br. s., 1 H) 3.37 (dd, J=13.20, 4.70 Hz, 1 H) 3.51 (dd, J=13.20, 3.80Hz, 1 H) 3.64 (d, J=12.00 Hz, 1 H) 3.76 (d, J=12.00 Hz, 1 H) 4.32 (m,J=3.70, 3.70, 3.70 Hz, 1 H) 4.37 (d, J=3.20 Hz, 1 H) 4.58 (d, J=12.01Hz, 1 H) 4.81 (d, J=12.01 Hz, 1 H) 4.86 (s, 1 H) 7.16-7.44 (m, 5 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 26.4, 27.3, 52.1, 63.4, 69.6, 80.9, 81.8,92.5, 102.1, 116.3, 127.5, 127.6, 128.2, 137.6. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₁₆H₂₂N₃O₅ ⁺ 336.15540; Found 336.1561.

((3aR,4R,6R,6aR)-6-(azidomethyl)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methylmethanesulfonate (6)

A solution of the top anomer of 5 (500 mg, 1.5 mmol) in CH₂Cl₂ (15 mL)containing triethylamine (280 μL, 2 mmol) was placed under a nitrogenatmosphere and cooled to 0° C. on ice. Methanesulfonyl chloride (132 μL,1.7 mmol) was added. After stirring for 2 h the mixture was transferredto a separatory funnel, diluted with EtOAc (50 mL) and washed with HCl(1M, 40 mL), NaHCO₃ (sat. aq., 40 mL). The organic layer was separated,dried (Na₂SO₄), concentrated in vacuo and purified by silica gelchromatography (toluene/EtOAc 1:4) to yield the title compound (590 mg,1.42 mmol, 94.7%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.45(s, 3 H) 1.49 (s, 3 H) 2.95 (s, 3 H) 3.31 (dd, J=12.6, 6.7 Hz, 1 H) 3.51(dd, J=12.6, 8.1 Hz, 1 H) 4.28-4.35 (m, 1 H) 4.39-4.56 (m, 4 H) 4.78 (d,J=11.7 Hz, 1 H) 5.17 (s, 1 H) 7.23-7.43 (m, 5 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.7, 27.8, 37.4, 53.5, 68.6, 70.1, 84.7, 85.4, 92.2,107.8, 114.9, 128.16, 128.17, 128.6, 136.4. HRMS (ESI-TOF) m/z: [M+Na]⁺Calcd for C₁₇H₂₃N₃NaO₇S⁺ 436.11489; Found 436.1159.

(3aR,4R,6R,6aR)-3a,6-bis(azidomethyl)-4-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole(7)

Methanesulfonic ester 6 (590 mg, 1.42 mmol) was taken up in DMF (50 mL)and NaN₃ (1.4 g, 21.3 mmol) was added. The mixture was stirred at 90° C.for 48 h. The mixture was allowed to cool to rt and taken to dryness.The residue was dissolved in Et₂O (30 mL) and water (30 mL) andtransferred to a separatory funnel. The layers were separated and theaqueous layer was extracted once with Et₂O (30 mL). All ether fractionswere pooled, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by silica gel chromatography (hexane/EtOAc 100:0→90:10)yielding the compound (356 mg, 1.0 mmol, 70%) as a colorless viscousoil. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.49 (s, 3 H) 1.50 (s, 3 H) 3.27 (dd,J=12.6, 6.7 Hz, 1 H) 3.44-3.56 (m, 2 H) 3.66 (d, J=13.2, 1 H) 4.30 (t,J=7.18 Hz, 1 H) 4.38 (s, 1 H) 4.54 (d, J=11.6 Hz, 1 H) 4.79 (d, J=11.6Hz, 1 H) 5.19 (s, 1 H) 7.24-7.42 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.8, 28.2, 53.0, 53.8, 70.3, 85.4, 93.9, 108.2, 114.9, 128.20, 128.23,128.7, 136.7. HRMS (ESI-TOF) m/z: [M+H—N₂]⁺ Calcd for C₁₆H₂₁N₄O₄ ⁺333.15573; Found 333.1568.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(3,4,5-tris(benzyloxy)benzamide)(8)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (s,3 H) 1.50 (s, 3 H) 3.58-3.70 (m, 1 H) 3.70-3.82 (m, 2 H) 4.08 (dd,J=14.6, 6.7 Hz, 1 H) 4.44-4.54 (m, 2 H) 4.63 (s, 1 H) 4.76 (d, J=11.8Hz, 1 H) 4.98-5.08 (m, 12 H) 5.19 (s, 1 H) 6.53 (t, J=6.0 Hz, 1 H) 6.99(t, J=5.9 Hz, 1 H) 7.03 (s, 2 H) 7.17 (s, 2 H) 7.17-7.27 (m, 12 H)7.27-7.38 (m, 23 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 28.0, 41.4,42.5, 70.5, 71.3, 71.4, 75.2, 75.3, 84.9, 85.0, 93.9, 106.9, 107.1,109.1, 113.5, 127.6, 127.7, 127.9, 127.96, 128.04, 128.1, 128.22,128.24, 128.3, 128.57, 128.60, 128.7, 129.4, 129.5, 136.6, 136.7, 136.8137.5, 137.6, 141.4, 141.6, 152.8, 153.0, 167.3, 167.6. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₇₂H₆₉N₂O₁₂ ⁺ 1153.4845; Found: 1153.4854.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(3,4,5-trimethoxybenzamide)(9)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.43 (s,3 H) 1.50 (s, 3 H) 3.54-3.79 (m, 3 H) 3.81 (s, 6 H) 3.82 (s, 6 H) 3.86(s, 3 H) 3.87 (s, 3 H) 4.15 (dd, J=14.7, 7.2 Hz, 1 H) 4.47-4.59 (m, 2 H)4.62 (s, 1 H) 4.83 (d, J=11.6 Hz, 1 H) 5.23 (s, 1 H) 6.67 (t, J=6.1 Hz,1 H) 6.94 (s, 2 H) 7.04 (s, 2 H) 7.09 (t, J=5.7 Hz, 1 H) 7.23-7.31 (m, 5H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 28.0, 41.3, 42.44, 56.30, 56.31,60.9, 61.0, 70.5, 84.7, 84.9, 94.0, 104.4, 104.6, 109.2, 113.4, 127.9,128.2, 128.7, 129.5, 129.6, 136.8, 141.0, 141.2, 153.1, 153.3, 167.5,167.8. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₃₆H₄₄N₂NaO₁₂ 719,27865;Found: 719,2809.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(3,4-bis(benzyloxy)benzamide)(10)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (s,3 H) 1.47 (s, 3 H) 3.48-3.59 (m, 1 H) 3.73-3.85 (m, 2 H) 3.98 (dd,J=14.5, 6.3 Hz, 1 H) 4.45 (t, J=6.8 Hz, 1 H) 4.52 (d, J=11.6 Hz, 1 H)4.57 (s, 1 H) 4.78 (d, J=11.6 Hz, 1 H) 5.09 (s, 2 H) 5.10-5.12 (m, 4 H)5.15 (s, 2 H) 5.20 (s, 1 H) 6.56 (t, J=5.5 Hz, 1 H) 6.78 (d, J=2.3 Hz, 1H) 6.81 (d, J=2.3 Hz, 1 H) 6.89 (t, J=5.7 Hz, 1 H) 7.05 (d, J=8.36 Hz, 1H) 7.18-7.43 (m, 26 H) 7.47 (d, J=1.6 Hz, 1 H) 7.53 (d, J=2.0 Hz, 1 H).¹³C NMR (75 MHz, CDCl3) δ ppm 27.7, 28.0, 41.4, 42.3, 70.5, 71.9, 71.0,71.2, 71.3, 84.9, 85.0, 93.9, 109.1, 113.4, 113.6, 113.8, 114.0, 114.1,120.0, 120.3, 127.0, 127.1, 127.19, 127.23, 127.5, 127.9, 127.99,128.02, 128.06, 128.2, 128.5, 128.6, 128.7, 128.8, 136.71, 136.80 (br),137.0, 148.8, 148.9, 151.7, 151.9, 167.0, 167.2. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₅₈H₅₇N₂O₁₀ ⁺ 941,40077; Found: 941,4030.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(3,5-bis(benzyloxy)benzamide)(11)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.40 (s,3 H) 1.48 (s, 3 H) 3.58-3.76 (m, 2 H) 3.81 (dd, J=14.5, 5.7 Hz, 1 H)4.04 (dd, J=14.5, 6.6 Hz, 1 H) 4.45 (t, J=7.0 Hz, 1 H) 4.54 (d, J=12.0Hz, 1 H) 4.58 (s, 1 H) 4.78 (d, J=11.7 Hz, 1 H) 4.96 (s, 4 H) 4.98 (s, 4H) 5.19 (s, 1 H) 6.58 (t, J=6.0 Hz, 1 H) 6.68 (t, J=2.1 Hz, 1 H) 6.70(t, J=2.1 Hz, 1 H) 6.88 (t, J=5.7 Hz, 1 H) 6.93 (d, J=2.1 Hz, 2 H) 7.04(d, J=2.1 Hz, 2 H) 7.14-7.38 (m, 25 H); ¹³C NMR (75 MHz, CDCl₃) δ ppm27.7, 28.0, 41.6, 42.5, 70.3, 70.4, 70.5, 84.9, 85.1, 93.9, 105.4,105.6, 106.1, 106.2, 109.0, 113.6, 127.6, 127.7, 128.0, 128.1, 128.24,128.28, 128.66, 128.71, 128.8, 136.3, 136.4, 136.5, 136.6, 136.8, 160.1,160.2, 167.3, 167.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₅₈H₅₇N₂O₁₀ ⁺941,40077; Found: 941,4005.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(3-(benzyloxy)benzamide)(12)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (s,3 H) 1.49 (s, 3 H) 3.53-3.67 (m, 1 H) 3.74-3.89 (m, 2 H) 4.04 (dd,J=14.4, 6.6 Hz, 1 H) 4.02-4.02 (m, 1 H) 4.48 (t, J=7.0 Hz, 1 H)4.52-4.60 (m, 2 H) 4.81 (d, J=11.5 Hz, 1 H) 5.04 (s, 2 H) 5.05 (s, 2 H)5.22 (s, 1 H) 6.63 (t, J=6.1 Hz, 1 H) 6.90 (t, J=5.9 Hz, 1 H) 7.03-7.11(m, 2 H) 7.12-7.17 (m, 1 H) 7.22-7.43 (m, 19 H) 7.45-7.51 (m, 1 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.7, 28.0, 41.5, 42.4, 70.2, 70.3, 70.6,84.9, 85.0, 93.9, 109.2, 113.47, 113.54, 113.57, 118.7, 118.8, 118.9,119.2, 127.67, 127.69, 128.15, 128.24, 128.28, 128.35, 128.70, 128.74,128.86, 129.7, 129.9, 135.5, 135.6, 136.6, 136.7, 136.8, 159.1, 159.2,167.4, 167.5. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₄₄H₄₄N₂NaO₈ ⁺751.29899; Found: 751.3020.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(4-(benzyloxy)benzamide)(13)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.39 (s,3 H) 1.47 (s, 3 H) 3.47-3.60 (m, 1 H) 3.77-3.91 (m, 2 H) 4.00 (dd,J=14.5, 6.3 Hz, 1 H) 4.47 (t, J=7.0 Hz, 1 H) 4.54 (d, J=11.4 Hz, 1 H)4.59 (s, 1 H) 4.80 (d, J=11.6 Hz, 1 H) 5.05 (s, 2 H) 5.07 (s, 2 H) 5.22(s, 1 H) 6.70 (t, J=6.2 Hz, 1 H) 6.92 (t, J=7.7 Hz, 4 H) 7.04 (t, J=5.8Hz, 1 H) 7.24-7.44 (m, 15 H) 7.63 (d, J=8.7 Hz, 2 H) 7.72 (d, J=8.9 Hz,2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 41.3, 42.2, 70.08,70.14, 70.4, 84.88, 84.89, 93.9, 109.2, 113.4, 114.6, 114.8, 126.5,126.6, 127.50, 127.53, 128.19, 128.24, 128.3, 128.69, 128.72, 128.75,128.76, 128.78, 129.0, 129.1, 136.3, 136.4, 136.9, 161.4, 161.5, 167.0,167.1. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₄₄H₄₄N₂NaO₈ ⁺ 751.29899,found: 751.3013.

N,N′-(((3aR,4R,6R,6aR)-4-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))dibenzamide(14)

General procedure 1. White foam. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (s,3 H) 1.49 (s, 3 H) 3.53-3.64 (m, 1 H) 3.78-3.89 (m, 2 H) 4.03 (dd,J=14.4, 6.4 Hz, 1 H) 4.49 (t, J=7.0 Hz, 1 H) 4.54-4.61 (m, 2 H) 4.82 (d,J=11.3 Hz, 1 H) 5.24 (s, 1 H) 6.71 (t, J=6.0 Hz, 1 H) 6.98 (t, J=5.4 Hz,1 H) 7.27-7.52 (m, 11 H) 7.63-7.71 (m, 2 H) 7.71-7.80 (m, 2 H). ¹³C NMR(75 MHz, CDCl₃) δ ppm 27.7, 28.0, 41.5, 42.4, 70.6, 85.0, 94.0, 109.2,113.5, 127.0, 127.1, 128.35, 128.36, 128.6, 128.8, 128.9, 131.6, 131.8,134.0, 134.1, 136.8, 167.6, 167.7. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd forC₃₀H₃₂N₂NaO₆ ⁺ 539.21526, found: 539.2169.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(3,4,5-trihydroxybenzamide)(15)

General procedure 2. White foam. (56:44 mixture of anomers)¹H NMR (300MHz, D₂O) δ 3.38-3.55 (m, 2.56 H), 3.71-3.88 (m, 2 H), 4.00 (d, J=8.1Hz, 0.44 H), 4.01-4.16 (m, 1 H), 6.63 (s, 1.12 H), 6.65 (s, 1.12 H),6.73 (s, 0.88 H); ¹³C NMR (75 MHz, D₂O) δ ppm 39.4, 40.7, 41.1, 41.7,70.6, 71.6, 77.5, 79.1, 79.9, 80.0, 97.7, 101.6, 106.96, 107.00, 107.11,107.18, 123.9, 124.1, 124.5, 124.6, 136.2 (br.), 136.3 (br.), 144.3,144.5, 169.9, 170.1, 170.2, 170.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₃N₂O₁₂ ⁺ 483,12455; Found: 483,1250.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(3,4,5-trimethoxybenzamide)(16)

General procedure 2. White foam. (70:30 mixture of anomers)¹H NMR (300MHz, CD₃OD) δ 3.50-3.90 (m, 22.30 H), 4.08-4.19 (m, 1.70H), 5.14 (s,0.70 H), 5.22 (s 0.30 H), 7.12-7.18 (m, 4 H). ¹³C NMR (75 MHz, CD₃OD) δppm 42.7, 43.0, 44.9, 45.9, 56.8 (br.), 61.2 (br.), 74.8, 75.3, 79.2,81.3, 81.7, 82.4, 99.7, 103.1, 105.9, 106.12, 106.15, 106.18, 130.7,130.8, 130.9, 131.0, 142.0, 142.1, 142.2, 142.3, 154.3, 154.4, 154.5,154.6, 169.9, 170.0, 170.5, 170.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₆H₃₅N₂O₁₂ ⁺ 567,21845; Found: 483,1250.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(3,4-dihydroxybenzamide)(17)

General procedure 2. White foam. (55:45 mixture of anomers)¹H NMR (300MHz, D₂O) δ ppm 3.37-3.57 (m, 2.58 H) 3.69-3.88 (m, 2 H) 4.01 (d, J=7.9Hz, 0.45 H) 4.09-4.18 (m, 1 H) 5.23 (s, 0.45 H) 5.28 (s, 0.55 H)6.62-6.81 (m, 2 H) 6.92-7.04 (m, 2.70 H) 7.06-7.15 (m, 1.30 H). ¹³C NMR(75 MHz, D₂O) δ ppm 29.5, 39.4, 40.6, 41.2, 41.6, 70.7, 71.5, 77.5,79.1, 79.8, 80.0, 97.6, 101.6, 114.3, 114.4, 114.5, 114.6, 115.1, 115.2,115.30, 115.4, 120.0, 120.1, 120.2, 120.3, 124.7, 124.8, 125.1, 125.2,143.43 (br.), 143.5, 143.6, 147.7 (br.), 147.8, 169.9, 170.0, 170.1,170.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₃N₂O₁₀ ⁺ 451,13472;Found: 451,1346.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(3,5-dihydroxybenzamide)(18)

General procedure 2. White foam. (54:46 mixture of anomers)¹H NMR (300MHz, D₂O) δ 3.37-3.60 (m, 2.54 H), 3.74-3.88 (m, 2 H), 4.00 (d, J=7.91Hz, 0.46 H), 5.23 (s, 0.46 H), 5.30 (s, 0.54 H); 6.35 (s, 0.54 H), 6.39(s, 0.54 H), 6.41 (s, 0.46H), 6.44 (s, 0.46 H), 6.52 (s, 1.08 H), 6.53(s, 1.08 H), 6.58 (s, 0.92 H), 6.64 (s, 0.92 H). ¹³C NMR (75 MHz, D₂O) δppm 39.5, 40.6, 41.3, 41.7, 70.7, 71.4, 77.4, 79.0, 79.8, 80.0, 97.6,101.6, 105.9 (v br.), 106.0, 135.0, 135.2, 135.5, 135.7, 156.75, 156.77,156.80, 156.84, 170.0, 170.2, 170.3, 170.4. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₀H₂₃N₂O₁₀ ⁺ 451,13472; Found: 451,1344.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(3-hydroxybenzamide)(19)

General procedure 2. White foam. (51:49 mixture of anomers)¹H NMR (300MHz, D₂O) δ ppm 3.38-3.59 (m, 2.51 H) 3.68-3.82 (m, 2 H) 4.03 (d, J=7.9Hz, 0.49 H) 4.09-4.20 (m, 1 H) 5.21 (s, 0.51 H) 5.27 (s, 0.49 H)6.85-6.99 (m, 3 H) 7.02-7.25 (m, 5 H). ¹³C NMR (75 MHz, D₂O) d ppm 39.9,40.9, 41.8, 42.0, 71.4, 72.0, 77.4, 79.1, 79.9, 78.0, 97.6, 101.3,113.49, 113.50, 113.58, 113.61, 118.70, 118.78, 118.97, 119.03, 129.88,129.91, 129.96 (br), 134.25, 134.38, 134.61 (br), 155.42, 155.44, 155.5(br), 170.2, 170.4, 170.51, 170.53. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₃N₂O₈ ⁺ 419,14489; Found: 419,1447.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(4-hydroxybenzamide)(20)

General procedure 2. White foam. (68:32 mixture of anomers)¹H NMR (300MHz, CD₃OD) δ ppm 3.48-3.63 (m, 2.32 H) 3.65-3.79 (m, 2 H) 4.05 (d,J=7.6 Hz, 0.68 H) 4.08-4.16 (m, 1 H) 5.11 (s, 0.68 H) 5.19 (s, 0.32 H)6.76-6.86 (m, 4 H) 7.64-7.77 (m, 4 H). ¹³C NMR (75 MHz, CD₃OD) δ ppm42.8 (br.), 44.5, 45.9, 74.8, 75.3, 79.3, 81.3, 81.7, 82.3, 99.7, 103.2,116.2, 116.3 (br.), 126.2 (br.), 126.37, 126.42, 130.4, 130.5 (br.),130.6, 162.18, 162.24, 162.3 (br.), 170.3, 170.5, 171.0, 171.2. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₃N₂O₈ ⁺ 419,14489; Found: 419,1455.

N,N′-(((2R,3R,4R)-3,4,5-trihydroxytetrahydrofuran-2,4-diyl)bis(methylene))dibenzamide(21)

General procedure 2. White foam. (67:33 mixture of anomers)¹H NMR (300MHz, CD₃OD) δ ppm 3.52-3.72 (m, 2.67 H) 3.72-3.87 (m, 2 H) 4.11 (d,J=7.6 Hz, 0.68 H) 4.14-4.22 (m, 1 H) 5.19 (s, 0.68 H) 5.26 (s, 0.32 H)7.35-7.52 (m, 6 H) 7.75-7.88 (m, 4 H). ¹³C NMR (75 MHz, CD₃OD) δ ppm42.8, 42.9, 44.5, 45.8, 74.9, 75.3, 79.0, 81.0, 81.5, 82.1, 99.6, 103.1,128.31, 128.36, 128.41, 128.43, 129.55, 129.60, 129.62, 129.64, 132.70,132.79, 132.83 (br.), 135.34, 135.37, 135.45, 135.52, 170.3, 170.5,171.0, 171.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₃N₂O₆ ⁺387,15506; Found: 387,1549.

((R)-5-((R)-2-azido-1-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4,4-diyl)dimethanol(22)

Sodium borohydride (5.0 g, 133.1 mmol) was added to a stirred and cooled(0° C.) solution of compound 3 (13.1 g, 53.2 mmol) in MeOH (400 mL). Thereaction mixture was allowed to attain ambient temperature and wasstirred for 12 h, at which time TLC (CH₂Cl₂/MeOH 94:6) showed theconsumption of starting material. Ammonium chloride (25.0 g) was addedto quench the excess of borohydride. The resulting suspension wasstirred for 2 h, concentrated and adsorbed onto celite. Purification byflash chromatography (CH₂Cl₂/MeOH 95:5) afforded triol 22 as a whitepowder in 92.7% yield. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.36 (s, 3 H) 1.39(s, 3 H) 3.29-3.38 (m, 1 H) 3.46 (dd, J=12.6, 2.1 Hz, 1 H) 3.59-3.76 (m,4 H) 3.90-3.99 (m, 2 H). ¹³C NMR (75 MHz, CD₃OD) δ ppm 26.8, 28.6, 56.0,62.2, 64.6, 70.0, 79.4, 85.7, 109.6. HRMS (ESI-TOF) m/z: [M+NH₄]⁺ Calcdfor C₃H₂₁N₄O₅ ⁺ 265.15065; Found 265.1501.

((3aR,6R,6aR)-6-(Azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl4-methylbenzenesulfonate (23)

To a stirred solution of triol 22 (5.0 g, 20.1 mmol) in pyridine (100mL) was added p-toluenesulfonylchloride (8.4 g, 44.1 mmol). The reactionmixture was stirred at room temperature for 3 h and then heated to 60°C. overnight, after which time TLC analysis (hexane/EtOAc 3:1) showedthe presence of a major product. The resulting suspension was filteredand the residue was concentrated under reduced pressure. The crudematerial was then purified by flash column chromatography (hexane/EtOAc4:1) to afford tosylate 23 as a colorless oil in 71.5% yield. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.34 (s, 3 H) 1.49 (s, 3 H) 2.46 (s, 3 H) 3.37(app. d, J=5.0 Hz, 2 H) 3.83 (app. s, 2 H) 4.11 (d, J=10.3 Hz, 1 H) 4.17(app. td, J=5.1, 2.1 Hz, 1 H) 4.22 (d, J=10.5 Hz, 1 H) 4.41 (d, J=2.1Hz, 1 H) 7.34-7.41 (m, 2 H) 7.79-7.85 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃)δ ppm 21.5, 27.1, 27.7, 51.4, 69.2, 74.5, 83.9, 84.3, 90.1, 115.0,127.9, 129.9, 132.2, 145.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₆H₂₂N₃O₆S⁺ 384.12238; Found 384.1229.

2-(((3aS,6R,6aR)-6-(Azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)isoindoline-1,3-dione(24)

To a solution of compound 23 (4.1 g, 10.7 mmol) in DMF (100 mL) wasadded a catalytic amount of NaI, followed by potassium phthalimide (4.0g, 21.4 mmol). The reaction mixture was heated to 90° C. and stirredovernight, after which TLC analysis (toluene/EtOAc 4:1) showed theformation of a major product. The solvent was evaporated under reducedpressure and the residue was taken up in EtOAc and washed with water.The organic layer was dried over sodium sulphate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (toluene/EtOAc 95:5) to afford compound 24 as a paleyellow oil, which solidified on standing (86.2%). ¹H NMR (300 MHz,CDCl₃) δ ppm 1.29 (s, 3 H) 1.49 (s, 3 H) 3.42-3.55 (m, 2 H) 3.96 (d,J=10.3 Hz, 1 H) 4.06 (app. s, 2 H) 4.10 (d, J=10.3 Hz, 1 H) 4.17 (app.td, J=5.3, 2.1 Hz, 1 H) 4.63 (d, J=2.1 Hz, 1 H) 7.72-7.79 (m, 2 H)7.86-7.92 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.5, 27.6, 41.0,51.9, 75.8, 84.0, 85.6, 91.6, 114.2, 123.3, 131.6, 134.1, 168.2. HRMS(ESI-TOF) m/z: [M+NH4]⁺ Calcd for C₁₇H₂₂N₅O₅ ⁺ 376.16155; Found376.1601.

((3aS,6R,6aR)-6-(Azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methanamine(25)

Hydrazine monohydrate (0.54 mL, 11.2 mmol) was added dropwise to astirred solution of compound 24 (1.60 g, 4.46 mmol) in 50 mL of EtOH.The solution was heated to reflux for 4 h, after which time TLC analysis(CH₂Cl₂/MeOH 9:1 or toluene/EtOAc 4:1) showed complete consumption ofstarting material and the presence of a major product. The mixture wasallowed to attain room temperature, concentrated and adsorbed ontocelite. Purification by flash chromatography (CH₂Cl₂/MeOH/20% NH₄OH92:8:0.1) afforded compound 25 as a colorless oil in 93.3% yield. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.43 (s, 3 H) 1.53 (m, 5 H) 2.91-3.04 (m, 2 H)3.42 (d, J=5.3 Hz, 2 H) 3.92 (s, 2 H) 4.21 (td, J=5.1, 2.1 Hz, 1 H) 4.35(d, J=2.3 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 45.7,51.7, 75.9, 84.1, 84.8, 93.3, 113.7.

N-(((3aS,6R,6aR)-6-(Azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(26)

To a cooled (0° C.) solution of compound 25 (1.8 g, 7.9 mmol) in 100 mLof CH₂Cl₂ were added triethylamine (2.2 mL, 15.8 mmol) and benzoylchloride (1.0 mL, 8.7 mmol) and the reaction mixture was stirred for 3hours. The solvent was evaporated, after which the residue was taken upin EtOAc and washed with 0.1 M aq. HCl and sat. aq. NaHCO₃ solution. Theorganic layer was dried over sodium sulphate, filtered and concentrated.The residue was purified by flash column chromatography (toluene/EtOAc7:3) to afford compound 26 as a colorless syrup (98.3%). ¹H NMR (300MHz, CDCl₃) δ ppm 1.43 (s, 3 H) 1.55 (s, 3 H) 3.40-3.56 (m, 2 H) 3.75(dd, J=14.1, 5.6 Hz, 1 H) 3.92 (dd, J=14.1, 6.4 Hz, 1 H) 3.96 (s, 2 H)4.23 (ddd, J=6.4, 4.6, 1.9 Hz, 1 H) 4.39 (d, J=2.1 Hz, 1 H) 6.59 (t,J=5.1 Hz, 1 H) 7.42-7.56 (m, 3 H) 7.77-7.83 (m, 2 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.9, 28.1, 43.5, 52.1, 76.0, 84.3, 85.3, 92.2, 114.3,127.0, 128.9, 132.0, 134.0, 167.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₆H₂₁N₄O₄ ⁺ 333.15573; Found 333.1554.

N-(((3aS,6R,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-2-chlorobenzamide(27)

General procedure 4. Colourless oil, 69.2% ¹H NMR (300 MHz, CDCl₃) δ ppm1.41 (s, 3 H) 1.54 (s, 3 H) 3.44 (dd, J=12.9, 5.0 Hz, 1 H) 3.53 (dd,J=13.1, 6.3 Hz, 1 H) 3.85 (app. dd, J=6.2, 1.8 Hz, 2 H) 3.99 (app. s, 2H) 4.24 (ddd, J=6.4, 4.8, 2.1 Hz, 1 H) 4.41 (d, J=2.1 Hz, 1 H) 6.60 (t,J=6.0 Hz, 1 H) 7.31-7.45 (m, 3 H) 7.65-7.69 (m, 1 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.9, 28.0, 43.7, 51.9, 75.9, 84.2, 85.4, 92.0, 114.3,127.2, 130.0, 130.4, 130.7, 131.6, 134.8, 167.0. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₁₆H₂₀ClN₄O₄ ⁺ 367.11676; Found 367.1167.

N-(((3aS,6R,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(28)

General procedure 4. Colourless oil, 80.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.45 (s, 3 H) 1.56 (s, 3 H) 3.46 (dd, J=12.9, 5.0 Hz, 1 H) 3.55 (dd,J=13.0, 6.3 Hz, 1 H) 3.77 (dd, J=14.1, 5.6 Hz, 1 H) 3.89-4.01 (m, 3 H)4.20-4.28 (m, 1 H) 4.40 (d, J=2.1 Hz, 1 H) 6.58 (t, J=6.0 Hz, 1 H)7.37-7.50 (m, 3 H) 7.58-7.64 (m, 2 H) 7.65-7.71 (m, 2 H) 7.84-7.90 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.9, 28.0, 43.4, 51.9, 75.8, 84.2,85.2, 92.2, 114.2, 127.2, 127.4, 127.5, 128.1, 129.0, 132.6, 139.9,144.7, 167.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₂₃N₄O₄ ⁺409.18703; Found 409.1856.

N-(((3aS,6R,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)pyridazine-4-carboxamide(29)

General procedure 4. Colourless oil, 83.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.39 (s, 3 H) 1.53 (s, 3 H) 3.44-3.57 (m, 2 H) 3.82-4.03 (m, 4 H) 4.23(app. td, J=5.1, 2.2 Hz, 1 H) 4.45 (d, J=2.1 Hz, 1 H) 7.89 (t, J=6.0 Hz,1 H) 7.96 (dd, J=5.3, 2.3 Hz, 1 H) 9.36 (dd, J=5.3, 1.5 Hz, 1 H) 9.61(dd, J=2.3, 1.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9,43.8, 52.1, 75.8, 84.1, 85.3, 91.9, 114.5, 124.4, 131.8, 148.6, 152.0,164.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₄H₁₃N₆O₄ ⁺ 335.14623;Found 335.1459.

N-(((3aS,6R,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-2-phenylacetamide(30)

General procedure 4. Colourless oil, 79.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.14 (s, 3 H) 1.46 (s, 3 H) 3.28-3.45 (m, 3 H) 3.61 (s, 2 H) 3.71-3.87(m, 3 H) 4.13-4.21 (m, 2 H) 5.89 (t, J=6.0 Hz, 1 H) 7.23-7.39 (m, 5 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.8, 42.6, 43.9, 51.8, 75.7, 84.2,84.9, 92.0, 113.8, 127.6, 129.2, 129.5, 134.5, 171.4. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₁₇H₂₃N₄O₄ ⁺ 347.17138; Found 347.1710.

N-(((3aS,6R,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-3-phenylpropanamide(31)

General procedure 4. Colourless oil, 79.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.32 (s, 3 H) 1.49 (s, 3 H) 2.52 (t, J=7.5 Hz, 2 H) 2.98 (t, J=7.3 Hz, 2H) 3.30-3.67 (m, 4 H) 3.74-3.84 (m, 2 H) 4.14-4.20 (m, 2 H) 5.86 (t,J=5.6 Hz, 1 H) 7.16-7.32 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8,27.9, 31.6, 38.4, 42.9, 51.8, 75.7, 84.1, 85.1, 92.0, 114.0, 126.4,128.4, 128.7, 140.7, 172.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₈H₂₅N₄O₄ ⁺ 361.18703; Found 361.1878.

N-(((3aS,6R,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-N-methylbenzamide(32)

A flask containing a solution of azide 26 (0.15 g, 0.45 mmol) in THF (5mL) was purged with nitrogen gas and treated with NaH (60% dispersion inmineral oil, 22 mg, 0.54 mmol). After 1 hour, MeI (56 μL, 0.90 mmol) wasadded and the RM was stirred at RT overnight, after which massspectrometry (ESI-TOF) analysis indicated incomplete consumption of SMand the formation of the desired compound. Further NaH (18 mg, 0.45mmol) and MeI (56 μL, 0.90 mmol) were added and the mixture was stirredfor 24 h. Solid particles were separated by filtration and the filtratewas adsorbed onto celite. Purification via flash column chromatography(toluene/EtOAc 100:0→70:30) gave the title compound in 68.4% yield(colourless oil). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.46 (s, 3 H) 1.55 (s, 3H) 3.13 (s, 3 H) 3.43 (dd, J=12.9, 4.7 Hz, 1 H) 3.61 (dd, J=12.7, 7.8Hz, 1 H) 3.81 (d, J=14.4 Hz, 1 H) 3.91-4.09 (m, 3 H) 4.25 (br. s., 1 H)4.53 (app. s, 1 H) 7.38-7.44 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.6, 27.9, 40.6, 51.3, 51.5, 75.7, 84.4, 85.2, 93.4, 113.7, 126.8,128.6, 129.8, 136.0, 172.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₇H₂₃N₄O₄ ⁺ 347.17138; Found 347.1700.

N-(((3aS,6R,6aR)-6-(Aminomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(33)

Azide 26 was subjected to general procedure 3. Crude amine was usedwithout further purification.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-methylbenzamide(34)

General procedure 4. White foam, 79.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.50 (s, 3 H) 2.36 (s, 3 H) 3.42 (ddd, J=13.9, 6.7, 5.1Hz, 1 H) 3.73 (app. td, J=14.4, 6.6 Hz, 2 H) 3.83-4.00 (m, 3 H) 4.27(app. t, J=7.0 Hz, 1 H) 4.53 (d, J=1.2 Hz, 1 H) 7.18 (d, J=7.9 Hz, 2 H)7.32 (dd, J=6.4, 5.6 Hz, 1 H) 7.36-7.58 (m, 4 H) 7.75 (d, J=8.2 Hz, 2 H)7.85-7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 21.5, 27.7, 27.8,39.7, 43.1, 74.9, 83.7, 85.1, 92.3, 113.3, 127.25 (2C), 128.7, 129.2,131.2, 131.8, 133.8, 142.1, 168.06, 168.12. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₉N₂O₅ ⁺ 425.20710; Found 425.2072.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-fluorobenzamide(35)

General procedure 4. White foam, 81.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.46 (ddd, J=14.1, 6.6, 5.1 Hz, 1 H)3.63-3.81 (m, 2 H) 3.85-3.98 (m, 3 H) 4.29 (app. td, J=6.9, 0.9 Hz, 1 H)4.51 (d, J=1.2 Hz, 1 H) 7.01-7.09 (m, 2 H) 7.39-7.47 (m, 3 H) 7.48-7.56(m, 2 H) 7.83-7.94 (m, 4 H). ¹⁹F NMR (282 MHz, CDCl3) δ ppm −108.5 (m).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.9, 43.2, 75.0, 83.6, 84.9,92.3, 113.5, 115.5 (d, J=21.6 Hz), 127.2, 128.7, 129.7 (d, J=8.9 Hz),130.2 (d, J=2.8 Hz), 132.0, 133.7, 164.8 (d, J=252.1 Hz), 167.0, 168.3.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₆FN₂O₅ ⁺ 429.18203; Found429.1828.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-chlorobenzamide(36)

General procedure 4. White foam, 74.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.50 (s, 3 H) 3.46 (ddd, J=14.1, 6.6, 5.1 Hz, 1 H)3.62-3.82 (m, 2 H) 3.84-3.98 (m, 3 H) 4.29 (app. t, J=6.6, 1 H) 4.51 (d,J=1.5 Hz, 1 H) 7.31-7.37 (m, 2 H) 7.39-7.55 (m, 4 H) 7.62 (t, J=6.0 Hz,1 H) 7.77-7.91 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.9,43.1, 75.0, 83.5, 84.9, 92.2, 113.5, 127.2, 128.70, 128.72, 128.8,132.0, 132.4, 133.6, 137.8, 167.1, 168.3. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₃H₂₆ClN₂O₅ ⁺ 445.15248; Found 445.1537.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-methoxybenzamide(37)

General procedure 4. White foam, 72.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.50 (s, 3 H) 3.42 (ddd, J=14.1, 6.6, 5.1 Hz, 1 H)3.66-3.79 (m, 2 H) 3.81 (s, 3 H) 3.85-3.97 (m, 3 H) 4.27 (app. t, J=7.2Hz, 1 H) 4.54 (d, J=1.2 Hz, 1 H) 6.83-6.91 (m, 2 H) 7.34 (t, J=5.9 Hz, 1H) 7.38-7.53 (m, 3 H) 7.56 (t, J=6.2 Hz, 1 H) 7.80-7.87 (m, 2 H)7.87-7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.7,43.1, 55.4, 74.9, 83.7, 85.1, 92.2, 113.3, 113.7, 126.3, 127.2, 128.6,129.1, 131.9, 133.7, 162.3, 167.6, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₉N₂O₆ ⁺ 441.20201; Found 441.2027.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-cyanobenzamide(38)

General procedure 4. White foam, 90.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.53 (app. dt, J=14.1, 5.9 Hz, 1 H) 3.63(dd, J=14.4, 5.6 Hz, 1 H) 3.76-3.98 (m, 4 H) 4.32 (app. t, J=6.4 Hz, 1H) 4.48 (d, J=1.5 Hz, 1 H) 7.25-7.34 (m, 1 H) 7.42-7.49 (m, 2 H)7.51-7.57 (m, 1 H) 7.68 (app. d, J=8.5 Hz, 2 H) 7.79-7.88 (m, 3 H) 8.02(app. d, J=8.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.9, 28.1, 40.3,43.3, 75.3, 83.5, 84.8, 92.4, 113.8, 115.1, 118.4, 127.3, 128.3, 129.0,132.4, 132.5, 133.6, 138.2, 166.4, 168.5. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₆N₃O₅ ⁺ 436.18670; Found 436.1869.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-(dimethylamino)benzamide(39)

General procedure 4. White foam, 72.2% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.50 (s, 3 H) 2.99 (s, 6 H) 3.37 (ddd, J=14.0, 6.2, 5.3Hz, 1 H) 3.69-3.80 (m, 2 H) 3.86-3.97 (m, 3 H) 4.25 (app. t, J=7.2 Hz, 1H) 4.56 (d, J=0.9 Hz, 1 H) 6.63 (app. d, J=8.8 Hz, 2 H) 6.92 (t, J=6.0Hz, 1 H) 7.38-7.53 (m, 3 H) 7.58 (t, J=6.2 Hz, 1 H) 7.72-7.79 (m, 2 H)7.89-7.97 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.6,40.2, 43.1, 75.0, 84.1, 85.3, 92.3, 111.1, 113.2, 120.6, 127.4, 128.6,128.7, 131.8, 133.9, 152.7, 168.0, 168.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₅H₃₂N₃O₅ ⁺ 454.23365; Found 454.2357.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-(trifluoromethyl)benzamide(40)

General procedure 4. White foam, 83.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.53 (ddd, J=14.1, 6.5, 5.1 Hz, 1 H) 3.65(dd, J=14.4, 5.6 Hz, 1 H) 3.77-3.98 (m, 4 H) 4.33 (app. td, J=6.7, 1.2Hz, 1 H) 4.49 (d, J=1.5 Hz, 1 H) 7.22 (t, J=6.3 Hz, 1 H) 7.41-7.48 (m, 2H) 7.50-7.56 (m, 1 H) 7.60-7.69 (m, 3 H) 7.82-7.88 (m, 2 H) 8.00 (d,J=8.2 Hz, 2 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm −63.3 (s). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.8, 27.9, 40.1, 43.2, 75.1, 83.4, 84.8, 92.3, 113.7,125.6 (q, J=3.7 Hz), 125.6 (q, J=272.6 Hz) (weak), 127.1, 127.9, 128.8,132.2, 133.3 (q, J=32.8 Hz), 133.6, 137.4, 166.8, 168.3. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₄H₂₆F₃N₂O₅ ⁺ 479.17883; Found 479.1777.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)isonicotinamide(41)

General procedure 4. White foam, 73.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.52 (s, 3 H) 3.50-3.67 (m, 2 H) 3.77-3.97 (m, 4 H) 4.32(app. td, J=6.6, 1.2 Hz, 1 H) 4.48 (d, J=1.5 Hz, 1 H) 7.38-7.57 (m, 4 H)7.73-7.80 (m, 2 H) 7.82-7.89 (m, 2 H) 7.96 (t, J=5.9 Hz, 1 H) 8.63-8.72(m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 40.0, 43.1, 75.1,83.3, 84.6, 92.3, 113.6, 121.4, 127.1, 128.8, 132.1, 133.5, 141.3,150.4, 166.1, 168.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₆N₃O₅ ⁺412.18670; Found 412.1876.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(42)

General procedure 4. White foam, 65.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.49 (ddd, J=14.0, 6.7, 5.1 Hz, 1 H)3.67-3.85 (m, 2 H) 3.88-4.00 (m, 3 H) 4.32 (app. t, J=6.9 Hz, 1 H) 4.54(d, J=1.2 Hz, 1 H) 7.31-7.54 (m, 8 H) 7.54-7.65 (m, 4 H) 7.84-7.99 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 39.9, 43.2, 75.0, 83.7,85.1, 92.3, 113.5, 127.2, 127.26 (2C), 127.9, 128.1, 128.7, 129.0,132.0, 132.7, 133.8, 140.1, 144.4, 167.8, 168.2. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₉H₃₁N₂O₅ ⁺ 487.22275; Found 487.2219.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-methylbenzamide(43)

General procedure 4. White foam, 97.0% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 2.35 (s, 3 H) 3.44 (ddd, J=14.0, 7.0, 5.1Hz, 1 H) 3.66-3.80 (m, 2 H) 3.83-4.01 (m, 3 H) 4.29 (app. t, J=7.2 Hz, 1H) 4.52 (d, J=1.2 Hz, 1 H) 7.23-7.32 (m, 3 H) 7.36-7.56 (m, 4 H)7.58-7.71 (m, 2 H) 7.83-7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm21.4, 27.7, 27.8, 39.7, 43.2, 75.0, 83.7, 85.1, 92.3, 113.4, 124.3,127.2, 127.9, 128.4, 128.7, 131.9, 132.4, 133.7, 134.0, 138.4, 168.1,168.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₉N₂O₅ ⁺ 425.20710;Found 425.2079.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-fluorobenzamide(44)

General procedure 4. White foam, 78.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 3.51 (ddd, J=14.1, 6.7, 5.3 Hz, 1 H)3.63-3.82 (m, 2 H) 3.85-4.00 (m, 3 H) 4.31 (app. td, J=7.0, 1.0 Hz, 1 H)4.49 (d, J=1.2 Hz, 1 H) 7.13-7.27 (m, 2 H) 7.32-7.56 (m, 5 H) 7.58-7.69(m, 2 H) 7.82-7.91 (m, 2 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm −112.4 (m).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 39.9, 43.2, 75.1, 83.5, 84.8,92.3, 113.6, 114.7 (d, J=22.7 Hz), 118.7 (d, J=21.6 Hz), 122.9 (d, J=3.3Hz), 127.2, 128.8, 130.2 (d, J=7.7 Hz), 132.1, 133.6, 136.4 (d, J=7.2Hz), 162.8 (d, J=247.7 Hz), 166.7 (d, J=2.2 Hz), 168.3. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₃H₂₆FN₂O₅ ⁺ 429.18203; Found 429.1837.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-chlorobenzamide(45)

General procedure 4. White foam, 83.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.51 (ddd, J=14.0, 6.8, 5.0 Hz, 1 H) 3.65(dd, J=14.4, 5.3 Hz, 1 H) 3.77 (app. dt, J=14.1, 7.1 Hz, 1 H) 3.85-4.02(m, 3 H) 4.31 (app. td, J=7.0, 1.0 Hz, 1 H) 4.48 (d, J=1.2 Hz, 1 H) 7.18(t, J=6.2 Hz, 1 H) 7.30-7.56 (m, 6 H) 7.76 (app. dt, J=7.9, 1.3 Hz, 1 H)7.84-7.89 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 39.9,43.2, 75.2, 83.4, 84.8, 92.4, 113.6, 125.5, 127.2, 127.7, 128.9, 129.9,131.7, 132.1, 133.6, 134.7, 135.9, 166.7, 168.3. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₃H₂₆ClN₂O₅ ⁺ 445.15248; Found 445.1537.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-methoxybenzamide(46)

General procedure 4. White foam, 80.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.50 (s, 3 H) 3.45 (ddd, J=14.1, 6.7, 5.3 Hz, 1 H)3.63-3.82 (m, 5 H) 3.85-3.99 (m, 3 H) 4.29 (app. td, J=7.0, 0.9 Hz, 1 H)4.51 (d, J=1.2 Hz, 1 H) 7.01 (ddd, J=8.2, 2.6, 0.9 Hz, 1 H) 7.26-7.54(m, 8 H) 7.83-7.93 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.9, 28.0,40.0, 43.4, 55.6, 75.2, 83.8, 85.2, 92.4, 112.7, 113.6, 118.1, 119.4,127.4, 128.9, 129.7, 132.1, 133.9, 135.6, 160.0, 168.1, 168.3. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₉N₂O₆ ⁺ 441.20201; Found 441.2015.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-cyanobenzamide(47)

General procedure 4. White foam, 82.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 3.51-3.67 (m, 2 H) 3.74-4.00 (m, 4 H) 4.33(app. td, J=6.6, 0.8 Hz, 1 H) 4.50 (d, J=1.5 Hz, 1 H) 7.36 (t, J=6.3 Hz,1 H) 7.41-7.58 (m, 4 H) 7.75 (app. dt, J=7.8, 1.4 Hz, 1 H) 7.82-7.99 (m,3 H) 8.17 (app. dt, J=7.9, 1.5 Hz, 1 H) 8.27 (app. t, J=1.5 Hz, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 39.9, 43.1, 75.1, 83.2, 84.5,92.3, 112.6, 113.6, 118.2, 127.1, 128.8, 129.4, 131.3, 131.9, 132.1,133.4, 134.7, 135.2, 165.8, 168.4. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd forC₂₄H₂₅N₃NaO₅ ⁺ 458.16864; Found 458.1709.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-(dimethylamino)benzamide(48)

General procedure 4. White foam, 68.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 2.95 (s, 6 H) 3.43 (ddd, J=14.1, 6.9, 5.1Hz, 1 H) 3.67-3.82 (m, 2 H) 3.85-4.00 (m, 3 H) 4.27 (app. td, J=7.0, 0.9Hz, 1 H) 4.52 (d, J=1.5 Hz, 1 H) 6.83 (app. dd, J=7.9, 2.6 Hz, 1 H)6.99-7.13 (m, 2 H) 7.21-7.28 (m, 2 H) 7.31 (t, J=6.2 Hz, 1 H) 7.37-7.54(m, 3 H) 7.82-7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.78, 27.85,39.9, 40.6, 43.2, 75.0, 83.8, 85.2, 92.3, 111.4, 113.4, 114.5, 115.5,127.3, 128.7, 129.2, 131.9, 133.8, 134.9, 150.7, 168.0, 168.9. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₅H₃₂N₃O₅ ⁺ 454.23365; Found 454.2343.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-(trifluoromethyl)benzamide(49)

General procedure 4. White foam, 38.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.53 (ddd, J=14.1, 6.2, 5.1 Hz, 1 H) 3.63(dd, J=14.4, 5.6 Hz, 1 H) 3.80-4.00 (m, 4 H) 4.33 (app. td, J=6.7, 1.0Hz, 1 H) 4.50 (d, J=1.5 Hz, 1 H) 7.18 (t, J=6.3 Hz, 1 H) 7.40-7.48 (m, 2H) 7.49-7.58 (m, 2 H) 7.65 (t, J=6.0 Hz, 1 H) 7.73 (app. d, J=7.9 Hz, 1H) 7.80-7.90 (m, 2 H) 8.09 (app. d, J=7.9 Hz, 1 H) 8.20 (app. s, 1 H).¹⁹F NMR (282 MHz, CDCl₃) δ ppm −63.1 (s). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.8, 28.0, 40.1, 43.1, 75.2, 83.4, 84.7, 92.3, 113.6, 123.9 (q, J=272.6Hz) (weak), 124.52 (q, J=3.9 Hz), 127.1, 128.2 (q, J=3.9 Hz), 128.9,129.2, 130.8, 131.1 (q, J=32.8), 132.2, 133.5, 135.0, 166.6, 168.4. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₆F₃N₂O₅ ⁺ 479.17883; Found479.1787.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)nicotinamide(50)

General procedure 4. White foam, 84.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.53 (s, 3 H) 3.51-3.67 (m, 2 H) 3.82-4.02 (m, 4 H) 4.34(app. td, J=6.4, 1.5 Hz, 1 H) 4.47 (d, J=1.5 Hz, 1 H) 6.96 (t, J=6.3 Hz,1 H) 7.37 (ddd, J=8.0, 4.9, 0.9 Hz, 1 H) 7.40-7.58 (m, 4 H) 7.78-7.89(m, 2 H) 8.19-8.27 (m, 1 H) 8.72 (app. dd, J=5.0, 1.8 Hz, 1 H) 9.14 (dd,J=2.3, 0.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 28.0, 40.1,43.2, 75.2, 83.5, 84.7, 92.4, 113.8, 123.5, 127.1, 129.0, 129.9, 132.2,133.6, 135.4, 148.7, 152.4, 166.2, 168.3. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₂H₂₆N₃O₅ ⁺ 412.18670; Found 412.1866.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-[1,1′-biphenyl]-3-carboxamide(51)

General procedure 4. White foam, 67.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.50 (ddd, J=14.1, 6.6, 5.1 Hz, 1 H) 3.66(dd, J=14.4, 5.6 Hz, 1 H) 3.77-4.01 (m, 4 H) 4.32 (app. td, J=6.7, 0.9Hz, 1 H) 4.52 (d, J=1.5 Hz, 1 H) 7.20 (t, J=6.2 Hz, 1 H) 7.30-7.53 (m, 8H) 7.56-7.64 (m, 2 H) 7.67-7.74 (m, 1 H) 7.79-7.89 (m, 3 H) 8.13 (app.t, J=1.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 40.0, 43.2,75.2, 83.7, 85.0, 92.3, 113.5, 126.2, 126.2, 127.2, 127.3, 127.8, 128.8,129.0, 129.1, 130.4, 132.0, 133.7, 134.7, 140.4, 141.7, 168.0, 168.2.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₉H₃₁N₂O₅ ⁺ 487.22275; Found487.2245.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-methylbenzamide(52)

General procedure 4. White foam, 65.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 2.42 (s, 3 H) 3.31 (ddd, J=14.0, 7.5, 4.8Hz, 1 H) 3.62-3.76 (m, 2 H) 3.83-3.99 (m, 3 H) 4.22 (app. td, J=7.4, 1.0Hz, 1 H) 4.49 (d, J=1.2 Hz, 1 H) 6.75 (dd, J=6.9, 5.1 Hz, 1 H) 7.12-7.23(m, 2 H) 7.25-7.52 (m, 6 H) 7.80-7.88 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃)δ ppm 19.9, 27.78, 27.79, 39.5, 43.2, 74.8, 83.9, 85.3, 92.2, 113.5,125.8, 126.9, 127.2, 128.6, 130.1, 131.1, 131.8, 133.7, 135.9, 136.1,168.0, 170.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₉N₂O₅ ⁺425.20710; Found 425.2089.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-fluorobenzamide(53)

General procedure 4. White foam, 59.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.39 (s, 3 H) 1.52 (s, 3 H) 3.40-3.50 (m, 1 H) 3.72-3.85 (m, 2 H)3.88-3.98 (m, 3 H) 4.28 (app. t, J=7.3 Hz, 1 H) 4.50 (d, J=1.5 Hz, 1 H)7.10 (app. dd, J=11.1, 8.2 Hz, 1 H) 7.19-7.32 (m, 3 H) 7.38-7.52 (m, 4H) 7.84-7.90 (m, 2 H) 8.04 (app. td, J=7.9, 1.8 Hz, 1 H). ¹⁹F NMR (282MHz, CDCl₃) δ ppm −113.4 (m). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.79,27.85, 39.8, 43.3, 74.9, 83.8, 85.3, 92.3, 113.6, 116.2 (d, J=24.3 Hz),120.9 (d, J=11.6 Hz), 124.8 (d, J=2.8 Hz), 127.2, 128.6, 131.8, 131.9(d, J=1.7 Hz), 133.5 (d, J=9.4 Hz), 133.9, 162.6 (d, J=248.2 Hz), 164.0(d, J=2.8 Hz), 167.9. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₆FN₂O₅ ⁺429.18203; Found 429.1832.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-chlorobenzamide(54)

General procedure 4. White foam, 71.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.38 (ddd, J=14.1, 7.3, 5.0 Hz, 1 H)3.67-3.80 (m, 2 H) 3.85-3.95 (m, 3 H) 4.25 (app. td, J=7.2, 1.2 Hz, 1 H)4.51 (d, J=1.5 Hz, 1 H) 7.12 (dd, J=6.7, 5.0 Hz, 1 H) 7.23-7.57 (m, 8 H)7.79-7.86 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.8,43.2, 74.9, 83.6, 85.2, 92.2, 113.6, 127.0, 127.2, 128.6, 129.7, 130.3,130.9, 131.3, 131.8, 133.7, 135.1, 167.5, 168.0. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₃H₂₆ClN₂O₅ ⁺ 445.15248; Found 445.1539.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-methoxybenzamide(55)

General procedure 4. White foam, 64.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.53 (s, 3 H) 3.41 (ddd, J=13.9, 6.8, 5.1 Hz, 1 H)3.72-3.85 (m, 2 H) 3.86-4.00 (m, 6 H) 4.22-4.28 (app. t, J=7.3 Hz, 1 H)4.56 (d, J=1.4 Hz, 1 H) 6.96-7.00 (m, 1 H) 7.04-7.11 (m, 1 H) 7.38-7.53(m, 5 H) 7.87-7.95 (m, 2 H) 8.21 (dd, J=7.8, 1.9 Hz, 1 H) 8.27 (t, J=6.0Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.78, 27.81, 39.5, 43.3, 56.1,74.9, 84.2, 85.6, 92.2, 111.5, 113.4, 120.9, 121.3, 127.3, 128.6, 131.7,132.3, 133.3, 134.1, 157.7, 166.1, 167.8. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₉N₂O₆ ⁺ 441.20201; Found 441.2026.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-cyanobenzamide(56)

General procedure 4. White foam, 65.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.40 (s, 3 H) 1.49 (s, 3 H) 3.72-3.89 (m, 2 H) 3.92-4.01 (m, 2 H)4.03-4.14 (m, 2 H) 4.51 (app. t, J=7.8 Hz, 1 H) 4.61 (app. s, 1 H)7.39-7.85 (m, 9 H) 7.87-7.93 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.5, 28.0, 37.9, 43.2, 74.7, 82.4, 85.8, 92.5, 113.3, 121.4, 123.4,127.2, 128.6, 130.7, 131.7, 132.6, 133.3, 134.0, 137.5 (weak), 160.6,168.0, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₆N₃O₅ ⁺436.18670; Found 436.1870.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-(dimethylamino)benzamide(57)

General procedure 4. White foam, 64.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 2.72 (s, 6 H) 3.33 (ddd, J=13.8, 7.3, 5.0Hz, 1 H) 3.71-3.84 (m, 2 H) 3.89-4.05 (m, 3 H) 4.18-4.28 (app. t, J=7.8Hz, 1 H) 4.57 (app. s, 1 H) 7.12-7.26 (m, 2 H) 7.38-7.51 (m, 4 H) 7.65(t, J=5.9 Hz, 1 H) 7.88-7.99 (m, 2 H) 8.13 (dd, J=7.8, 1.6 Hz, 1 H)10.15 (dd, J=6.7, 5.3 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7,27.8, 39.2, 43.2, 45.4, 74.8, 84.2, 85.7, 92.2, 113.3, 120.1, 124.4,126.9, 127.3, 128.5, 131.3, 131.6, 132.3, 134.0, 152.6, 167.3, 167.8.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₅H₃₂N₃O₅ ⁺ 454.23365; Found454.2347.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-(trifluoromethyl)benzamide(58)

General procedure 4. White foam, 73.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.50 (s, 3 H) 3.28 (ddd, J=13.9, 7.0, 4.8 Hz, 1 H)3.60-3.77 (m, 2 H) 3.80-3.94 (m, 3 H) 4.20 (app. td, J=7.2, 0.9 Hz, 1 H)4.49 (d, J=1.2 Hz, 1 H) 7.17 (dd, J=7.0, 5.0 Hz, 1 H) 7.33-7.56 (m, 7 H)7.61-7.69 (m, 1 H) 7.75-7.83 (m, 2 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm−59.3 (s). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.7, 39.7, 43.0, 74.7,83.5, 85.1, 92.1, 113.5, 123.6 (q, J=273.7 Hz), 126.5 (q, J=5.0 Hz),127.1, 127.3 (q, J=32.1 Hz), 128.4, 128.6, 129.9, 131.8, 132.0, 133.5,135.4 (q, J=2.2 Hz), 168.0, 168.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₄H₂₆F₃N₂O₅ ⁺ 479.17883; Found 479.1797.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)picolinamide(59)

General procedure 4. White foam, 82.0% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.45 (ddd, J=13.6, 7.8, 5.6 Hz, 1 H)3.71-3.84 (m, 2 H) 3.89-4.03 (m, 3 H) 4.28 (app. td, J=7.3, 0.9 Hz, 1 H)4.54 (d, J=1.5 Hz, 1 H) 7.38-7.52 (m, 5 H) 7.82 (app. td, J=7.8, 1.8 Hz,1 H) 7.89-7.95 (m, 2 H) 8.16 (app. dt, J=7.8, 1.0 Hz, 1 H) 8.48 (t,J=6.4 Hz, 1 H) 8.52-8.58 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7,27.8, 39.2, 43.2, 74.8, 84.0, 85.5, 92.2, 113.4, 122.2, 126.4, 127.2,128.5, 131.6, 133.9, 137.3, 148.2, 149.4, 164.9, 167.8. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₂H₂₆N₃O₅ ⁺ 412.18670; Found 412.1878.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-[1,1′-biphenyl]-2-carboxamide(60)

General procedure 4. White foam, 69.0% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.47 (s, 3 H) 2.89-3.00 (m, 1 H) 3.42-3.65 (m, 3 H)3.74-3.89 (m, 3 H) 4.27 (d, J=1.2 Hz, 1 H) 6.13 (dd, J=7.3, 4.7 Hz, 1 H)7.27-7.53 (m, 12 H) 7.58-7.64 (m, 1 H) 7.77-7.85 (m, 2 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.7, 27.9, 39.4, 43.1, 74.5, 83.4, 85.3, 92.1, 113.3,127.2, 127.52 (2 C), 127.7, 128.56, 128.63, 128.66 (2 C), 130.3, 131.7,133.8, 135.4, 139.8, 140.1, 167.7, 170.3. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₉H₃₁N₂O₅ ⁺ 487.22275; Found 487.2243.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-bromobenzamide(61)

General procedure 4. White foam, 52.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.35 (ddd, J=14.1, 7.2, 4.8 Hz, 1 H)3.64-3.81 (m, 2 H) 3.85-3.97 (m, 3 H) 4.25 (app. td, J=7.2, 1.2 Hz, 1 H)4.53 (d, J=1.5 Hz, 1 H) 6.96 (dd, J=7.2, 4.8 Hz, 1 H) 7.20-7.34 (m, 3 H)7.36-7.59 (m, 5 H) 7.79-7.85 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.76, 27.84, 39.8, 43.3, 74.9, 83.6, 85.2, 92.2, 113.6, 119.4, 127.2,127.5, 128.7, 129.3, 131.3, 131.8, 133.4, 133.7, 137.7, 167.9, 168.5.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₆BrN₂O₅ ⁺ 489,10196; Found489.1030.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-iodobenzamide(62)

General procedure 4. White powder, 73.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 3.32 (ddd, J=14.0, 7.3, 4.8 Hz, 1 H)3.64-3.80 (m, 2 H) 3.85-3.97 (m, 3 H) 4.25 (app. td, J=7.1, 1.0 Hz, 1 H)4.56 (d, J=1.5 Hz, 1 H) 6.94 (dd, J=7.2, 4.8 Hz, 1 H) 7.06 (ddd, J=8.0,6.7, 2.3 Hz, 1 H) 7.29-7.43 (m, 5 H) 7.45-7.52 (m, 1 H) 7.79-7.86 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.76, 27.82, 39.7, 43.2, 74.9, 83.6,85.2, 92.2, 92.6, 113.5, 127.2, 128.16, 128.22, 128.7, 131.2, 131.8,133.7, 139.9, 141.8, 167.9, 170.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₃H₂₆1N₂O₅ ⁺ 537,08809; Found 537.0892.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3,4-dimethylbenzamide(63)

General procedure 4. White foam, 66.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.50 (s, 3 H) 2.25 (s, 3 H) 2.27 (s, 3 H) 3.42 (ddd,J=14.1, 6.7, 5.3 Hz, 1 H) 3.66-3.80 (m, 2 H) 3.84-3.99 (m, 3 H) 4.27(app. t, J=7.2 Hz, 1 H) 4.53 (d, J=1.2 Hz, 1 H) 7.14 (d, J=7.9 Hz, 1 H)7.20-7.27 (m, 1 H) 7.37-7.60 (m, 5 H) 7.63 (app. s, 1 H) 7.85-7.96 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 19.7, 19.8, 27.7, 27.8, 39.7, 43.2,75.0, 83.8, 85.1, 92.3, 113.3, 124.6, 127.3, 128.5, 128.6, 129.7, 131.5,131.8, 133.8, 136.9, 140.8, 168.1, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₅H₃₁N₂O₅ ⁺ 439.22275; Found 439.2233.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3,4-difluorobenzamide(64)

General procedure 4. White foam, 93.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.53 (ddd, J=14.1, 6.2, 5.1 Hz, 1 H) 3.63(dd, J=14.5, 5.4 Hz, 1 H) 3.72-4.00 (m, 4 H) 4.31 (app. td, J=6.6, 1.2Hz, 1 H) 4.47 (d, J=1.5 Hz, 1 H) 7.13-7.23 (m, 2 H) 7.42-7.59 (m, 4 H)7.65-7.72 (m, 1 H) 7.76-7.89 (m, 3 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm−136.9 (m), −133.2 (m). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 40.0,43.2, 75.2, 83.3, 84.7, 92.3, 113.6, 117.4 (dd, J=17.7, 3.0 Hz), 117.3(dd, J=18.2, 6.0 Hz), 124.1 (dd, J=6.9, 3.6 Hz), 127.1, 128.9, 131.3(dd, J=4.7, 3.6 Hz), 132.2, 133.5, 150.4 (dd, J=249.6, 13.0 Hz), 152.72(dd, J=254.3, 12.7 Hz), 165.9 (d, J=6.0 Hz), 168.4. HRMS (ESI-TOF) m/z:[M+Na]⁺ Calcd for C₂₃H₂₄F₂N₂NaO₅ ⁺ 469.15455; Found 469.1563.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3,4-dichlorobenzamide(65)

General procedure 4. White foam, 76.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.52 (s, 3 H) 3.47-3.57 (m, 1 H) 3.62 (dd, J=14.5, 5.4 Hz,1 H) 3.74-4.00 (m, 4 H) 4.31 (app. td, J=6.7, 0.9 Hz, 1 H) 4.48 (d,J=1.2 Hz, 1 H) 7.23 (t, J=6.2 Hz, 1 H) 7.39-7.57 (m, 4 H) 7.68 (t, J=6.0Hz, 1 H) 7.74 (dd, J=8.5, 2.1 Hz, 1 H) 7.81-7.92 (m, 2 H) 8.04 (d, J=2.1Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 40.0, 43.1, 75.2,83.3, 84.6, 92.3, 113.6, 126.7, 127.2, 128.9, 129.7, 130.5, 132.2,132.9, 133.5, 133.9, 136.0, 165.9, 168.4. HRMS (ESI-TOF) m/z: [M+Na]⁺Calcd for C₂₃H₂₄Cl₂N₂NaO₅ ⁺ 501.09545; Found 501.0978.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3,4-dimethoxybenzamide(66)

General procedure 4. White foam, 82.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.46 (ddd, J=14.1, 6.4, 5.3 Hz, 1 H)3.66-3.99 (m, 11 H) 4.29 (app. td, J=6.7, 0.9 Hz, 1 H) 4.52 (d, J=1.2Hz, 1 H) 6.84 (d, J=8.2 Hz, 1 H) 7.23-7.34 (m, 2 H) 7.37-7.57 (m, 5 H)7.82-7.93 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.9,43.1, 56.03 (2 C), 75.0, 83.8, 85.1, 92.3, 110.4, 110.7, 113.5, 120.2,126.6, 127.2, 128.7, 132.0, 133.7, 148.9, 151.9, 167.6, 168.1. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₅H₃₁N₂O₇ ⁺ 471.21258; Found 471.2130.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-1-naphthamide(67)

General procedure 4. White foam, 67.5% ¹H NMR (300 MHz, CDCl₃) (majorconformer) δ ppm 1.34 (s, 3 H) 1.49 (s, 3 H) 3.32 (ddd, J=13.9, 7.5, 5.0Hz, 1 H) 3.57 (dd, J=14.2, 5.4 Hz, 1 H) 3.73 (app. dt, J=14.0, 7.2 Hz, 1H) 3.79-3.91 (m, 3 H) 4.24 (app. t, J=7.2 Hz, 1 H) 4.51 (d, J=1.2 Hz, 1H) 7.19-7.25 (m, 1 H) 7.27-7.37 (m, 3 H) 7.38-7.55 (m, 5 H) 7.74-7.85(m, 4 H) 8.18-8.26 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.66, 27.74,39.6, 43.0, 74.7, 83.7, 85.2, 92.1, 113.4, 124.6, 125.2, 125.3, 126.3,127.0, 127.2, 128.3, 128.5, 130.0, 130.7, 131.7, 133.58, 133.64, 133.8,168.0, 170.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₇H₂₉N₂O₅ ⁺461.20710; Found 461.2088.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-naphthamide(68)

General procedure 4. White foam, 94.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.53 (ddd, J=14.0, 6.8, 5.2 Hz, 1 H) 3.71(dd, J=14.4, 5.7 Hz, 1 H) 3.77-3.99 (m, 4 H) 4.35 (app. td, J=7.0, 1.0Hz, 1 H) 4.56 (d, J=1.2 Hz, 1 H) 7.30-7.59 (m, 7 H) 7.76-7.98 (m, 6 H)8.34-8.44 (app. d, J=1.4 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8,27.9, 39.9, 43.2, 75.1, 83.7, 85.1, 92.3, 113.5, 123.9, 126.7, 127.2,127.74, 127.76, 127.9, 128.4, 128.7, 129.1, 131.3, 132.0, 132.7, 133.8,134.9, 168.15, 168.18. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₇H₂₉N₂O₅ ⁺461.20710; Found 461.2085.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-1-methyl-1H-indole-2-carboxamide(69)

General procedure 4. Pink foam, 57.5% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37(s, 3 H) 1.52 (s, 3 H) 3.44 (ddd, J=14.1, 6.7, 5.3 Hz, 1 H) 3.64-3.80(m, 2 H) 3.85-4.05 (m, 6 H) 4.30 (app. td, J=7.0, 1.2 Hz, 1 H) 4.49 (d,J=1.2 Hz, 1 H) 7.01 (app. s, 1 H) 7.09-7.22 (m, 3 H) 7.27-7.54 (m, 5 H)7.56-7.62 (m, 1 H) 7.81-7.91 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.8, 27.9, 31.7, 39.4, 43.3, 75.1, 83.7, 85.1, 92.3, 104.7, 110.2,113.5, 120.5, 122.0, 124.2, 126.1, 127.2, 128.8, 131.5, 132.0, 133.8,139.2, 163.2, 168.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₆H₃₀N₃O₅ ⁺464.21800; Found 464.2188.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-1-methyl-1H-indole-3-carboxamide(70)

General procedure 4. White foam, 71.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.34 (s, 3 H) 1.50 (s, 3 H) 3.42 (app. dt, J=13.9, 5.6 Hz, 1 H) 3.68 (s,3 H) 3.71-3.96 (m, 5 H) 4.28 (app. t, J=6.9 Hz, 1 H) 4.57-4.63 (d, J=0.9Hz, 1 H) 6.92 (t, J=5.9 Hz, 1 H) 7.14-7.34 (m, 3 H) 7.37-7.51 (m, 3 H)7.64 (t, J=6.2 Hz, 1 H) 7.73 (s, 1 H) 7.88-7.98 (m, 2 H) 8.11-8.17 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 33.5, 39.3, 43.3, 75.1,84.3, 85.3, 92.3, 110.1, 110.3, 113.6, 120.9, 121.7, 122.8, 125.9,127.3, 128.8, 131.9, 132.3, 134.0, 137.4, 165.8, 168.0. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₆H₃₀N₃O₅ ⁺ 464.21800; Found 464.2202.

N,N′-(((3aS,6R,6aR)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))dibenzamide (71)

General procedure 4. White foam, 82.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 3.46 (ddd, J=14.0, 7.0, 5.1 Hz, 1 H)3.66-3.82 (m, 2 H) 3.85-4.00 (m, 3 H) 4.29 (app. td, J=7.0, 0.9 Hz, 1 H)4.51 (d, J=1.2 Hz, 1 H) 7.23 (t, J=6.0 Hz, 1 H) 7.32 (t, J=6.2 Hz, 1 H)7.36-7.56 (m, 6 H) 7.77-7.95 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.8, 27.9, 39.8, 43.3, 75.0, 83.7, 85.1, 92.3, 113.5, 127.2, 127.3,128.6, 128.8, 131.7, 132.0, 133.8, 134.1, 168.05, 168.10. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₃H₂₇N₂O₅ ⁺ 411.19145; Found 411.1920.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((2-phenylacetamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(72)

General procedure 4. White foam, 81.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.49 (s, 3 H) 3.18 (ddd, J=14.1, 6.7, 5.2 Hz, 1 H)3.51-3.66 (m, 4 H) 3.75-3.88 (m, 3 H) 4.10 (app. td, J=6.4, 1.3 Hz, 1 H)4.37 (d, J=1.5 Hz, 1 H) 6.66 (dd, J=6.7, 5.3 Hz, 1 H) 7.20-7.33 (m, 6 H)7.37-7.54 (m, 3 H) 7.78-7.89 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.7, 27.9, 39.7, 43.0, 43.7, 75.0, 83.8, 84.9, 92.1, 113.6, 127.2,127.3, 128.7, 128.9, 129.4, 131.9, 133.8, 135.0, 168.0, 172.0. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₉N₂O₅ ⁺ 425.20710; Found 425.2075.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((3-phenylpropanamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(73)

General procedure 4. White foam, 68.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 2.57 (t, J=7.6 Hz, 2 H) 2.98 (t, J=7.6 Hz, 2H) 3.18-3.23 (m, 1 H) 3.56 (dd, J=14.4, 5.6 Hz, 1 H) 3.66 (ddd, J=14.1,7.5, 6.4 Hz, 1 H) 3.74-3.91 (m, 3 H) 4.10 (app. td, J=6.1, 1.3 Hz, 1 H)4.32 (d, J=1.5 Hz, 1 H) 6.47 (dd, J=6.7, 5.0 Hz, 1 H) 7.07 (t, J=6.2 Hz,1 H) 7.12-7.32 (m, 5 H) 7.39-7.58 (m, 3 H) 7.78-7.91 (m, 2 H). ¹³C NMR(75 MHz, CDCl₃) δ ppm 27.8, 28.0, 31.7, 38.4, 39.5, 42.9, 75.0, 83.9,84.8, 92.2, 113.7, 126.3, 127.2, 128.56, 128.59, 128.8, 132.0, 133.7,141.1, 168.0, 173.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₅H₃₁N₂O₅ ⁺439.22275; Found 439.2229.

N-(((3aS,6R,6aR)-6-(cyclohexanecarboxamidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(74)

General procedure 4. Light brown colored foam, 76.7% ¹H NMR (300 MHz,CDCl₃) δ ppm 1.18-1.52 (m, 11 H) 1.63-1.89 (m, 5 H) 2.16 (tt, J=11.6,3.4 Hz, 1 H) 3.17 (ddd, J=14.0, 6.7, 4.8 Hz, 1 H) 3.58 (app. dt, J=14.2,7.3 Hz, 1 H) 3.71 (dd, J=14.2, 5.7 Hz, 1 H) 3.82-3.98 (m, 3 H) 4.13(app. td, J=6.9, 0.8 Hz, 1 H) 4.43 (d, J=1.2 Hz, 1 H) 6.57 (dd, J=6.7,5.0 Hz, 1 H) 7.38-7.59 (m, 4 H) 7.85-7.94 (m, 2 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 25.69 (2 C), 25.8, 27.7, 27.8, 29.6, 29.7, 39.1, 43.1,45.3, 74.8, 83.8, 85.0, 92.1, 113.4, 127.3, 128.6, 131.8, 133.8, 168.0,177.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₃₃N₂O₅ ⁺ 417.23840;Found 417.2396.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,6-dichlorobenzamide(75)

General procedure 4. White foam, 27.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.53 (s, 3 H) 3.39 (ddd, J=14.1, 6.7, 4.7 Hz, 1 H) 3.68(dd, J=14.4, 5.6 Hz, 1 H) 3.81-4.01 (m, 4 H) 4.28 (app. td, J=6.9, 1.2Hz, 1 H) 4.55 (d, J=1.5 Hz, 1 H) 6.91 (dd, J=7.3, 4.7 Hz, 1 H) 7.13-7.32(m, 4 H) 7.35-7.45 (m, 2 H) 7.47-7.53 (m, 1 H) 7.75-7.83 (m, 2 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 39.8, 43.2, 75.0, 83.5, 85.0,92.1, 113.7, 127.2, 128.1, 128.7, 130.8, 132.0, 132.3, 133.6, 135.9,165.4, 167.9. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₅Cl₂N₂O₅ ⁺479.11350; Found 479.1126.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,4-dichlorobenzamide(76)

General procedure 4. White foam, 77.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.42 (ddd, J=14.1, 7.3, 5.0 Hz, 1 H)3.64-3.82 (m, 2 H) 3.85-3.94 (m, 3 H) 4.26 (app. td, J=7.0, 1.3 Hz, 1 H)4.47 (d, J=1.5 Hz, 1 H) 7.12-7.28 (m, 3 H) 7.36-7.54 (m, 5 H) 7.76-7.82(m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.95, 28.04, 40.2, 43.4, 75.2,83.7, 85.2, 92.4, 113.9, 127.3, 127.6, 128.9, 130.2, 131.0, 132.0,132.1, 133.7, 133.8, 136.9, 166.6, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₃H₂₅Cl₂N₂O₅ ⁺ 479.11350; Found 479.1135.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,4,6-trichlorobenzamide(77)

General procedure 4. White foam, 37.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.53 (s, 3 H) 3.42 (ddd, J=14.1, 6.2, 4.5 Hz, 1 H) 3.66(dd, J=14.4, 5.6 Hz, 1 H) 3.80-3.99 (m, 4 H) 4.29 (app. td, J=6.5, 1.4Hz, 1 H) 4.50 (d, J=1.5 Hz, 1 H) 7.13 (t, J=6.2 Hz, 1 H) 7.22 (dd,J=6.9, 4.5 Hz, 1 H) 7.30 (s, 2 H) 7.39-7.55 (m, 3 H) 7.73-7.79 (m, 2 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 28.1, 40.1, 43.3, 75.2, 83.4, 84.9,92.2, 113.9, 127.2, 128.3, 128.9, 132.2, 133.1, 133.5, 134.6, 135.9,164.8, 168.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₄Cl₃N₂O₅ ⁺513.07453; Found 513.0757.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3,5-dichloroisonicotinamide(78)

General procedure 4. White foam, 53.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.52 (s, 3 H) 3.41 (ddd, J=14.1, 5.8, 4.4 Hz, 1 H) 3.58(dd, J=14.4, 5.3 Hz, 1 H) 3.83-3.97 (m, 4 H) 4.28 (app. td, J=6.2, 1.5Hz, 1 H) 4.46 (d, J=1.8 Hz, 1 H) 7.21 (t, J=6.3 Hz, 1 H) 7.35-7.42 (m, 2H) 7.47-7.53 (m, 1 H) 7.68-7.73 (m, 2 H) 7.87 (dd, J=7.6, 4.4 Hz, 1 H)8.44 (s, 2 H). ¹³C NMR (75 MHz, CDCl3) δ ppm 27.5, 28.0, 39.9, 42.9,75.0, 83.1, 84.4, 92.1, 113.8, 127.0, 128.7, 129.0, 132.1, 133.3, 142.5,147.6, 163.0, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₄Cl₂N₃O₅⁺ 480.10875; Found 480.1098.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,4-dichloronicotinamide(79)

General procedure 4. White foam, 51.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.51 (s, 3 H) 3.39 (ddd, J=14.1, 5.9, 4.5 Hz, 1 H) 3.61(dd, J=14.4, 5.6 Hz, 1 H) 3.82-3.97 (m, 4 H) 4.27 (app. td, J=6.2, 1.3Hz, 1 H) 4.49 (d, J=1.8 Hz, 1 H) 7.22-7.28 (m, 2 H) 7.36-7.43 (m, 2 H),7.46-7.52 (m, 1 H) 7.71-7.76 (m, 2 H) 7.85 (dd, J=7.6, 4.4 Hz, 1 H) 8.22(d, J=5.3 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.5, 27.9, 39.9,43.0, 74.9, 83.2, 84.6, 92.0, 113.7, 123.7, 127.1, 128.7, 132.0, 132.3,133.3, 143.1, 148.8, 149.8, 163.8, 168.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₂H₂₄Cl₂N₃O₅ ⁺ 480.10875; Found 480.1087.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,6-dichloronicotinamide(80)

General procedure 4. White foam, 86.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.47 (ddd, J=14.1, 6.7, 4.7 Hz, 1 H) 3.64(dd, J=14.4, 5.6 Hz, 1 H) 3.76-3.93 (m, 4 H) 4.28 (app. t, J=6.5 Hz, 1H) 4.43 (d, J=1.5 Hz, 1 H) 7.10 (t, J=6.2 Hz, 1 H) 7.29 (d, J=7.9 Hz, 1H) 7.38-7.46 (m, 2 H) 7.48-7.56 (m, 1 H) 7.65 (dd, J=7.0, 4.7 Hz, 1 H)7.72-7.79 (m, 2 H) 7.93 (d, J=8.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δppm 27.7, 27.9, 40.3, 43.1, 75.0, 83.3, 84.6, 92.2, 113.8, 123.2, 127.0,128.8, 130.3, 132.0, 133.4, 141.3, 146.7, 151.4, 164.9, 168.1. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₄Cl₂N₃O₅ ⁺ 480.10875; Found480.1090.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4,6-dichloronicotinamide(81)

General procedure 4. White foam, 80.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.44 (ddd, J=14.1, 6.7, 4.7 Hz, 1 H) 3.63(dd, J=14.4, 5.6 Hz, 1 H) 3.77-3.92 (m, 4 H) 4.27 (app. td, J=6.4, 1.5Hz, 1 H) 4.45 (d, J=1.8 Hz, 1 H) 7.26-7.53 (m, 5 H) 7.72-7.78 (m, 2 H)7.83 (dd, J=7.0, 4.7 Hz, 1 H) 8.52 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃) δppm 27.6, 27.9, 40.1, 43.0, 74.9, 83.2, 84.6, 92.1, 113.7, 125.0, 127.0,128.6, 130.2, 131.9, 133.3, 143.0, 149.8, 152.9, 164.2, 168.1. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₄Cl₂N₃O₅ ⁺ 480.10875; Found480.1100.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-chloronicotinamide(82)

General procedure 4. White foam ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s, 3H) 1.51 (s, 3 H) 3.42 (ddd, J=14.0, 7.1, 4.7 Hz, 1 H) 3.66 (dd, J=14.4,5.6 Hz, 1 H) 3.73-3.93 (m, 4 H) 4.27 (app. td, J=6.7, 0.9 Hz, 1 H) 4.48(d, J=1.5 Hz, 1 H) 7.26 (dd, J=7.6, 4.7 Hz, 1 H) 7.33-7.52 (m, 4 H) 7.69(dd, J=6.9, 4.8 Hz, 1 H) 7.75-7.81 (m, 2 H) 7.91 (dd, J=7.6, 2.1 Hz, 1H) 8.37 (dd, J=4.8, 1.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6,27.8, 40.0, 43.1, 74.9, 83.3, 84.8, 92.1, 113.6, 122.5, 127.0, 128.6,131.7, 131.8, 133.5, 138.7, 147.4, 150.6, 165.8, 168.0. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₂H₂₅ClN₃O₅ ⁺ 446.14773; Found 446.1489.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-3-chloroisonicotinamide(83)

General procedure 4. White foam ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s, 3H) 1.52 (s, 3 H) 3.44 (ddd, J=14.1, 6.9, 4.8 Hz, 1 H) 3.63 (dd, J=14.4,5.9 Hz, 1 H) 3.75-3.92 (m, 4 H) 4.27 (app. t, J=6.6 Hz, 1 H) 4.45 (d,J=1.2 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.36-7.53 (m, 4 H) 7.69 (dd, J=6.7,5.0 Hz, 1 H) 7.73-7.80 (m, 2 H) 8.47 (app. d, J=5.0 Hz, 1 H) 8.56 (app.s, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 40.0, 43.1, 74.9,83.2, 84.6, 92.1, 113.7, 123.0, 127.0, 128.1, 128.6, 131.9, 133.5,142.0, 148.0, 150.2, 165.2, 168.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₂H₂₅ClN₃O₅ ⁺ 446.14773; Found 446.1493.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-4-chloronicotinamide(84)

General procedure 4. White foam ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s, 3H) 1.52 (s, 3 H) 3.45 (ddd, J=14.0, 7.0, 4.8 Hz, 1 H) 3.65 (dd, J=14.2,5.7 Hz, 1 H) 3.77-3.93 (m, 4 H) 4.28 (app. t, J=6.6 Hz, 1 H) 4.47 (d,J=1.5 Hz, 1 H) 7.25-7.34 (m, 2 H) 7.37-7.44 (m, 2 H) 7.46-7.53 (m, 1 H)7.67 (dd, J=6.7, 5.0 Hz, 1 H) 7.74-7.81 (m, 2 H) 8.45 (app. d, J=5.6 Hz,1 H) 8.73 (app. s, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 40.1,43.1, 74.9, 83.4, 84.8, 92.1, 113.7, 125.0, 127.1, 128.7, 131.3, 131.9,133.5, 141.2, 150.1, 151.4, 165.1, 168.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₂H₂₅ClN₃O₅ ⁺ 446.14773; Found 446.1476.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-6-chloronicotinamide(85)

General procedure 4. White foam, 57.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.51 (app. dt, J=14.4, 5.2 Hz, 1 H) 3.61(dd, J=14.4, 5.6 Hz, 1 H) 3.82-3.96 (m, 4 H) 4.30 (app. td, J=6.2, 1.2Hz, 1 H) 4.48 (d, J=1.5 Hz, 1 H) 7.31-7.57 (m, 5 H) 7.80-7.87 (m, 2 H)8.06 (dd, J=6.9, 4.8 Hz, 1 H) 8.18-8.24 (m, 1 H) 8.94 (app. dd, J=2.6,0.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.9, 40.1, 43.0,75.1, 83.3, 84.5, 92.2, 113.7, 124.1, 127.1, 128.77, 128.80, 132.2,133.4, 138.2, 149.0, 154.1, 165.3, 168.5. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₂H₂₅ClN₃O₅ ⁺ 446.14773; Found 446.1460.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyrimidine-2-carboxamide(86)

General procedure 4. Pale yellow foam, 50.8% ¹H NMR (300 MHz, CDCl₃) δppm 1.39 (s, 3 H) 1.52 (s, 3 H) 3.47 (ddd, J=13.9, 7.2, 5.6 Hz, 1 H)3.71-3.89 (m, 2 H) 3.94-4.04 (m, 3 H) 4.27 (app. td, J=7.3, 1.2 Hz, 1 H)4.54 (d, J=1.2 Hz, 1 H) 7.34 (t, J=6.2 Hz, 1 H) 7.39-7.53 (m, 4 H)7.88-7.94 (m, 2 H) 8.46 (t, J=6.3 Hz, 1 H) 8.89 (d, J=4.7 Hz, 2 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.6, 43.3, 74.8, 84.1, 85.8,92.3, 113.6, 122.8, 127.3, 128.7, 131.8, 133.8, 157.3, 157.6, 163.0,167.9. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₄O₅ ⁺ 413.18195;Found 413.1826.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyrimidine-4-carboxamide(87)

General procedure 4. Pale yellow foam, 52.8% ¹H NMR (300 MHz, CDCl₃) δppm 1.41 (s, 3 H) 1.53 (s, 3 H) 3.54 (ddd, J=13.9, 8.1, 5.6 Hz, 1 H)3.72-3.82 (m, 2 H) 3.89-3.99 (m, 3 H) 4.26-4.34 (m, 1 H) 4.45 (d, J=1.5Hz, 1 H) 6.99 (t, J=6.0 Hz, 1 H) 7.41-7.56 (m, 3 H) 7.82-7.89 (m, 2 H)8.10 (dd, J=5.0, 1.5 Hz, 1 H) 8.41 (t, J=6.2 Hz, 1 H) 8.97 (d, J=5.3 Hz,1 H) 9.25 (d, J=1.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 28.0,39.7, 43.5, 75.1, 83.8, 85.4, 92.3, 113.9, 118.7, 127.1, 128.7, 131.9,133.9, 156.0, 157.9, 159.3, 163.2, 167.9. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₁H₂₅N₄O₅ ⁺ 413.18195; Found 413.1816.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyrimidine-5-carboxamide(88)

General procedure 4. Pale yellow foam, 71.3% ¹H NMR (300 MHz, CDCl₃) δppm 1.36 (s, 3 H) 1.52 (s, 3 H) 3.50-3.61 (m, 2 H) 3.83-3.99 (m, 4 H)4.32 (app. td, J=5.8, 1.6 Hz, 1 H) 4.47 (d, J=1.8 Hz, 1 H) 7.38 (dd,J=6.7, 5.9 Hz, 1 H) 7.41-7.57 (m, 3 H) 7.79-7.87 (m, 2 H) 8.34 (dd,J=7.0, 4.7 Hz, 1 H) 9.27 (app. s, 1 H) 9.29 (app. s, 2 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.6, 28.0, 40.2, 42.9, 75.1, 83.2, 84.3, 92.2, 113.9,127.1, 127.7, 128.9, 132.3, 133.2, 156.3, 160.4 (weak), 164.3, 168.6.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₄O₅ ⁺ 413.18195; Found413.1828.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyridazine-3-carboxamide(89)

General procedure 4. White foam, 75.8% ¹H NMR (300 MHz, CDCl₃) δ ppm1.40 (s, 3 H) 1.53 (s, 3 H) 3.56 (ddd, J=13.8, 8.1, 5.6 Hz, 1 H)3.72-3.87 (m, 2 H) 3.91-4.03 (m, 3 H) 4.33 (app. t, J=7.3 Hz, 1 H) 4.53(d, J=1.5 Hz, 1 H) 7.18 (t, J=6.0 Hz, 1 H) 7.39-7.53 (m, 3 H) 7.67 (dd,J=8.5, 5.0 Hz, 1 H) 7.82-7.91 (m, 2 H) 8.29 (dd, J=8.5, 1.8 Hz, 1 H)8.65 (t, J=6.2 Hz, 1 H) 9.29 (dd, J=5.0, 1.8 Hz, 1 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.8, 28.0, 39.6, 43.3, 74.9, 83.9, 85.5, 92.3, 113.7,125.8, 127.1, 127.7, 128.6, 131.7, 133.9, 152.4, 152.9, 163.1, 167.8.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₄O₅ ⁺ 413.18195; Found413.1825.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyridazine-4-carboxamide(90)

General procedure 4. Yellow foam, 77.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.51-3.64 (m, 2 H) 3.82-3.99 (m, 4 H) 4.33(app. td, J=5.9, 1.4 Hz, 1 H) 4.49 (d, J=1.8 Hz, 1 H) 7.40-7.57 (m, 4 H)7.82-7.89 (m, 2 H) 8.07 (dd, J=5.3, 2.3 Hz, 1 H) 8.74 (dd, J=6.9, 4.8Hz, 1 H) 9.30 (dd, J=5.3, 1.2 Hz, 1 H) 9.73 (dd, J=2.2, 1.3 Hz, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 28.0, 40.3, 43.0, 75.1, 83.1, 84.4,92.2, 113.8, 124.5, 127.1, 128.8, 131.7, 132.2, 133.3, 149.2, 151.8,164.2, 168.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₄O₅ ⁺413.18195; Found 413.1819.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyrazine-2-carboxamide(91)

General procedure 4. White foam, 83.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.40 (s, 3 H) 1.53 (s, 3 H) 3.53 (ddd, J=13.8, 7.8, 5.7 Hz, 1 H)3.72-3.82 (m, 2 H) 3.87-4.00 (m, 3 H) 4.29 (app. t, J=7.0 Hz, 1 H) 4.48(d, J=1.2 Hz, 1 H) 7.15 (t, J=6.00 Hz, 1 H) 7.40-7.54 (m, 3 H) 7.82-7.91(m, 2 H) 8.26 (t, J=6.2 Hz, 1 H) 8.50-8.57 (m, 1 H) 8.75 (d, J=2.3 Hz, 1H) 9.39 (d, J=1.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9,39.4, 43.3, 74.9, 83.9, 85.3, 92.3, 113.7, 127.1, 128.6, 131.8, 133.8,142.7, 144.2, 144.4, 147.4, 163.6, 167.9. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₁H₂₅N₄O₅ ⁺ 413.18195; Found 413.1831.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide(92)

General procedure 4. White foam, 87.2% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.40 (app. dt, J=14.1, 5.7 Hz, 1 H) 3.63(dd, J=14.4, 5.6 Hz, 1 H) 3.71-3.98 (m, 4 H) 4.14 (s, 3 H) 4.28 (app. t,J=6.2 Hz, 1 H) 4.48 (d, J=1.2 Hz, 1 H) 6.80 (d, J=2.1 Hz, 1 H) 7.38-7.56(m, 5 H) 7.63 (dd, J=6.9, 5.4 Hz, 1 H) 7.82-7.91 (m, 2 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.6, 27.8, 39.26, 39.33, 42.9, 75.0, 83.3, 84.7,92.1, 107.1, 113.4, 127.1, 128.6, 132.0, 133.5, 135.0, 137.5, 160.5,168.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₇N₄O₅ ⁺ 415.19760;Found 415.1985.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-1-methyl-1H-imidazole-5-carboxamide(93)

General procedure 4. White foam, 94.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.51 (s, 3 H) 3.37 (app. dt, J=14.1, 5.6 Hz, 1 H) 3.61(dd, J=14.4, 5.3 Hz, 1 H) 3.70-4.00 (m, 7 H) 4.26 (app. t, J=6.3 Hz, 1H) 4.50 (d, J=1.2 Hz, 1 H) 7.36-7.53 (m, 4 H) 7.63-7.75 (m, 2 H)7.83-7.98 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 28.0, 34.4,39.3, 43.1, 75.4, 83.6, 84.8, 92.4, 113.7, 126.1, 127.1, 128.9, 132.2,132.5, 133.6, 141.9, 161.0, 168.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₇N₄O₅ ⁺ 415.19760; Found 415.1991.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-(methylsulfonamidomethyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(94)

General procedure 5. White foam, 77.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 2.96 (s, 3 H) 3.25-3.40 (m, 2 H) 3.74 (dd,J=14.4, 6.2 Hz, 1 H) 3.82-3.94 (m, 3 H) 4.19 (app. td, J=5.6, 1.6 Hz, 1H) 4.45 (d, J=1.8 Hz, 1 H) 5.96 (t, J=6.3 Hz, 1 H) 7.02 (t, J=6.3 Hz, 1H) 7.40-7.54 (m, 3 H) 7.77-7.84 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.9, 28.1, 40.7, 43.1, 43.7, 75.4, 84.1, 84.6, 92.4, 114.1, 127.3,128.9, 132.2, 133.8, 168.5. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd forC₁₇H₂₃N₂O₆S⁻ 383.12823; Found 383.1270.

N-(((3aS,6R,6aR)-6-(ethylsulfonamidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(95)

General procedure 5. White foam, 77.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.32 (t, J=7.3 Hz, 3 H) 1.37 (s, 3 H) 1.51 (s, 3 H) 3.03 (q, J=7.3 Hz, 2H) 3.20-3.35 (m, 2 H) 3.74 (dd, J=14.4, 6.2 Hz, 1 H) 3.80-3.96 (m, 3 H)4.17 (app. td, J=5.8, 1.3 Hz, 1 H) 4.48 (d, J=1.5 Hz, 1 H) 5.89 (t,J=6.3 Hz, 1 H) 7.15 (t, J=6.3 Hz, 1 H) 7.39-7.53 (m, 3 H) 7.77-7.86 (m,2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 8.2, 27.6, 27.8, 42.9, 43.4, 47.1,75.1, 84.0, 84.4, 92.1, 113.7, 127.1, 128.6, 131.9, 133.6, 168.2. HRMS(ESI-TOF) m/z: [M−H]⁻ Calcd for C₁₈H₂₅N₂O₆S⁻ 397.14388; Found 397.1423.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-(((1-methylethyl)sulfonamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(96)

General procedure 5. White foam, 36.0% ¹H NMR (300 MHz, CDCl₃) δ ppm1.28-1.42 (m, 9 H) 1.52 (s, 3 H) 3.18 (sep, J=6.9 Hz, 1 H) 3.25-3.41 (m,2 H) 3.74 (dd, J=14.5, 6.0 Hz, 1 H) 3.84-3.96 (m, 3 H) 4.18 (app. td,J=5.7, 1.5 Hz, 1 H) 4.46 (d, J=1.5 Hz, 1 H) 5.52 (dd, J=7.3, 5.3 Hz, 1H) 6.93 (t, J=6.3 Hz, 1 H) 7.41-7.55 (m, 3 H) 7.77-7.86 (m, 2 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 16.66, 16.71, 27.7, 27.9, 43.0, 44.0, 53.8,75.3, 84.2, 84.4, 92.3, 113.8, 127.1, 128.8, 132.0, 133.7, 168.2. HRMS(ESI-TOF) m/z: [M−H]⁻ Calcd for C₁₉H₂₇N₂O₆S⁻ 411.15953; Found 411.1585.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-(((trifluoromethyl)sulfonamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(97)

General procedure 5. White foam, 16.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.33 (s, 3 H) 1.54 (s, 3 H) 3.43-3.57 (m, 2 H) 3.60-3.70 (m, 1 H) 3.90(q, J=9.7 Hz, 2 H) 4.10 (dd, J=14.9, 7.9 Hz, 1 H) 4.24 (app. td, J=4.3,1.8 Hz, 1 H) 4.36 (d, J=1.8 Hz, 1 H) 6.84 (t, J=6.3 Hz, 1 H) 7.44-7.59(m, 3 H) 7.76-7.85 (m, 2 H) 7.92 (br.s., 1 H). ¹⁹F NMR (282 MHz, CDCl₃)δ ppm −77.9 (s). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.5, 28.3, 42.6, 45.2,75.7, 82.9, 83.7, 92.3, 114.2, 120.0 (q, J=321.2 Hz), 127.2, 129.1,132.6, 133.1, 169.1. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd for C₁₇H₂₀F₃N₂O₆S⁻437.09997; Found 437.0984.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-(phenylsulfonamidomethyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(98)

General procedure 5. White foam, 60.0% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.48 (s, 3 H) 3.07 (app. dt, J=13.6, 5.6 Hz, 1 H) 3.21(ddd, J=13.6, 8.0, 5.4 Hz, 1 H) 3.65-3.88 (m, 4 H) 4.13 (app. td, J=5.6,1.5 Hz, 1 H) 4.44 (d, J=1.8 Hz, 1 H) 6.11 (dd, J=7.8, 5.1 Hz, 1 H) 6.96(t, J=6.2 Hz, 1 H) 7.34-7.59 (m, 6 H) 7.72-7.93 (m, 4 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.7, 27.9, 43.0, 43.6, 75.3, 83.6, 84.5, 92.2, 113.8,127.0, 127.1, 128.8, 129.2, 132.0, 132.7, 133.7, 140.1, 168.3. HRMS(ESI-TOF) m/z: [M−H]⁻ Calcd for C₂₂H₂₅N₂O₆S⁻ 445.14388; Found 445.1421.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-(((4-methylphenyl)sulfonamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(99)

General procedure 5. White powder, 86.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.34 (s, 3 H) 1.47 (s, 3 H) 2.38 (s, 3 H) 2.98-3.21 (m, 2 H) 3.67-3.85(m, 4 H) 4.12 (app. td, J=5.9, 1.3 Hz, 1 H) 4.47 (d, J=1.5 Hz, 1 H) 6.10(dd, J=7.6, 5.3 Hz, 1 H) 7.09 (t, J=6.2 Hz, 1 H) 7.23 (d, J=8.2 Hz, 2 H)7.35-7.43 (m, 2 H) 7.45-7.52 (m, 1 H) 7.70 (d, J=8.2 Hz, 2 H) 7.76-7.83(m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 21.6, 27.8, 27.9, 43.2, 43.7,75.4, 83.6, 84.6, 92.3, 113.9, 127.14 (2 C), 128.8, 129.9, 132.0, 133.8,137.1, 143.5, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₉N₂O₆S⁺461.17408; Found 461.1738.

N-(((3aS,6R,6aR)-6-(((4-chlorophenyl)sulfonamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide (100)

General procedure 5. White foam, 90.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.48 (s, 3 H) 3.09 (app. dt, J=13.7, 5.5 Hz, 1 H) 3.22(ddd, J=13.6, 8.0, 5.4 Hz, 1 H) 3.69 (dd, J=14.4, 6.2 Hz, 1 H) 3.75-3.90(m, 3 H) 4.13 (app. td, J=5.5, 1.6 Hz, 1 H) 4.42 (d, J=1.8 Hz, 1 H) 6.37(dd, J=7.8, 5.1 Hz, 1 H) 6.95 (t, J=6.2 Hz, 1 H) 7.36-7.56 (m, 5 H)7.71-7.86 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 43.0,43.7, 75.3, 83.5, 84.4, 92.2, 113.9, 127.1, 128.5, 128.8, 129.4, 132.1,133.6, 138.8, 139.0, 168.4. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd forC₂₂H₂₄ClN₂O₆S⁻ 479.10491; Found 479.1047.

N-(((3aS,6R,6aR)-6-(((2-chlorophenyl)sulfonamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(101)

General procedure 5. White foam, 76.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.34 (s, 3 H) 1.46 (s, 3 H) 3.04 (ddd, J=13.7, 7.0, 5.1 Hz, 1 H) 3.17(ddd, J=13.6, 7.8, 5.6 Hz, 1 H) 3.68 (dd, J=14.4, 6.2 Hz, 1 H) 3.75-3.89(m, 3 H) 4.12 (app. t, J=6.3 Hz, 1 H) 4.45 (d, J=1.5 Hz, 1 H) 6.23 (dd,J=7.6, 5.0 Hz, 1 H) 7.04 (t, J=6.2 Hz, 1 H) 7.30-7.53 (m, 6 H) 7.73-7.83(m, 2 H) 7.96-8.03 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.8,43.0, 43.3, 75.1, 83.3, 84.4, 92.1, 113.7, 127.0, 127.2, 128.6, 131.0,131.4, 131.6, 131.8, 133.6, 133.8, 137.1, 168.1. HRMS (ESI-TOF) m/z:[M−H]⁻ Calcd for C₂₂H₂₄ClN₂O₆S⁻ 479.10491; Found 479.1055.

N-(((3aS,6R,6aR)-6-(([1,1′-biphenyl]-4-sulfonamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(102)

General procedure 5. White foam, 66.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 3 H) 1.48 (s, 3 H) 3.13 (dt, J=13.8, 5.6 Hz, 1 H) 3.25 (ddd,J=13.6, 7.8, 5.3 Hz, 1 H) 3.73 (dd, J=14.4, 6.2 Hz, 1 H) 3.78-3.91 (m, 3H) 4.16 (app. td, J=5.6, 1.5 Hz, 1 H) 4.47 (d, J=1.8 Hz, 1 H) 6.22 (dd,J=7.3, 5.3 Hz, 1 H) 6.98 (t, J=6.3 Hz, 1 H) 7.31-7.52 (m, 6 H) 7.52-7.60(m, 2 H) 7.61-7.71 (m, 2 H) 7.75-7.85 (m, 2 H) 7.85-7.96 (m, 2 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 43.1, 43.7, 75.3, 83.6, 84.5,92.2, 113.8, 127.1, 127.4, 127.6, 127.8, 128.5, 128.7, 129.1, 132.0,133.7, 138.7, 139.4, 145.5, 168.3. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd forC₂₈H₂₃N₂O₆S⁻ 521.17518; Found 521.1768.

N-(((3aS,6R,6aR)-6-(((2-bromophenyl)sulfonamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(103)

General procedure 5. White foam, 79.2% ¹H NMR (300 MHz, CDCl₃) δ ppm1.34 (s, 3 H) 1.46 (s, 3 H) 2.97-3.07 (m, 1 H) 3.15 (ddd, J=13.6, 7.7,5.7 Hz, 1 H) 3.68 (dd, J=14.2, 6.0 Hz, 1 H) 3.74-3.91 (m, 3 H) 4.12(app. t, J=6.3, 1 H) 4.45 (d, J=1.8 Hz, 1 H) 6.20 (dd, J=7.6, 5.0 Hz, 1H) 7.04 (t, J=6.2 Hz, 1 H) 7.31-7.53 (m, 5 H) 7.64-7.71 (m, 1 H)7.73-7.85 (m, 2 H) 7.99-8.06 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.66, 27.74, 43.0, 43.2, 75.0, 83.3, 84.4, 92.1, 113.6, 119.7, 127.0,127.8, 128.6, 131.3, 131.8, 133.6, 133.7, 135.1, 138.6, 168.0. HRMS(ESI-TOF) m/z: [M−H]⁻ Calcd for C₂₂H₂₄BrN₂O₆S⁻ 523.05439; Found523.0547.

N-(((3aS,6R,6aR)-6-(([1,1′-biphenyl]-2-sulfonamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(104)

To a solution of compound 103 (0.33 g, 0.63 mmol) in a 10:1 mixture ofDMF and H₂O were added K₂CO₃ (0.24 g, 1.76 mmol) and phenyl boronic acid(0.12 g, 0.95 mmol) and the flask was flushed with nitrogen gas. Afteraddition of a catalytic amount of Pd(PPh₃)₄ the reaction mixture wasstirred at 110° C. overnight. The reaction mixture was concentratedunder reduced pressure and purified by flash column chromatography(toluene/EtOAc 100:0→70:30). The title compound was obtained as a whitefoam in 45.6% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.34 (s, 3 H) 1.45(s, 3 H) 2.64-2.75 (m, 1 H) 2.84 (ddd, J=13.4, 8.0, 5.6 Hz, 1 H)3.60-3.80 (m, 4 H) 3.93 (ddd, J=7.0, 5.6, 1.5 Hz, 1 H) 4.22 (app. dd,J=7.9, 5.3 Hz, 1 H) 4.28 (d, J=1.8 Hz, 1 H) 6.75 (t, J=6.2 Hz, 1 H) 7.32(dd, J=7.5, 1.3 Hz, 1 H) 7.38-7.61 (m, 10 H) 7.74-7.82 (m, 2 H) 8.05(dd, J=7.9, 1.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9,43.1, 43.2, 75.0, 83.6, 84.7, 92.1, 113.9, 127.1, 128.0, 128.3, 128.6,128.7, 129.2, 129.3, 131.9, 132.47, 132.49, 133.9, 138.1, 138.8, 140.5,167.8. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd for C₂₈H₂₉N₂O₆S⁻ 521.17518;Found 521.1757.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(105)

To a solution of compound 26 (0.19 g, 0.56 mmol) in 5.5 mL of a mixtureof DMF/H₂O/TEA (4:1:0.5) were added a catalytic amount of Cu(I)I andTBTA, along with phenylacetylene (0.18 mL, 1.68 mmol). The reactionmixture was stirred for 4 h at 75° C., after which time TLC(toluene/EtOAc 1:1) showed no starting material. The reaction mixturewas concentrated under reduced pressure. The residue was taken up inethyl acetate and washed with 0.1M aq. HCl and sat. aq. NHCO₃ solution.The organic layer was dried over sodium sulphate, filtered andconcentrated. Purification by flash column chromatography (toluene/EtOAc3:2) afforded triazole 105 in 83.9% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 3 H) 1.50 (s, 3 H) 3.67-3.80 (2× dd, J=14.3, 6.6 Hz, J=14.3,6.2 Hz, 2 H) 3.87-3.97 (2× d, J=10.3 Hz, 2 H) 4.46-4.69 (m, 4 H) 6.90(t, J=6.2 Hz, 1 H) 7.27-7.55 (m, 6 H) 7.75-7.88 (m, 4 H) 7.99 (s, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 43.0, 50.7, 75.3, 83.5, 84.3,92.1, 114.3, 121.3, 125.9, 127.1, 128.2, 128.8, 128.9, 130.6, 132.0,133.7, 148.0, 168.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₇N₄O₄ ⁺435.20268; Found 435.2034.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((5-phenyl-1H-1,2,3-triazol-1-yl)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(106)

To a solution of compound 26 (0.17 g, 0.51 mmol) in 1,4-dioxane (5 mL)was added phenylacetylene (0.056 mL, 0.51 mmol). The flask was purgedwith nitrogen gas, sealed and heated to 60° C. A catalytic amount ofCpRuCl(PPh₃)₂ was dissolved in 0.5 mL of 1,4-dioxane and added to thereaction mixture, which was further stirred for 24 hours at 60° C. Thereaction mixture was concentrated under reduced pressure and adsorbedonto celite. Purification by flash column chromatography afforded thetriazole 106 in 82.6% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s, 3 H)1.46 (s, 3 H) 3.51-3.70 (m, 3 H) 3.78 (d, J=10.5 Hz, 1 H) 4.38-4.57 (m,3 H) 4.66 (d, J=1.5 Hz, 1 H) 7.02 (t, J=6.2 Hz, 1 H) 7.34-7.55 (m, 8 H)7.69 (s, 1 H) 7.78-7.89 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.74,27.78, 42.9, 48.0, 74.9, 83.7, 84.7, 92.1, 113.9, 126.8, 127.09, 127.10,128.7, 129.1, 129.2, 129.6, 131.8, 133.9, 139.0, 167.8. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₄H₂₇N₄O₄ ⁺ 435.20268; Found 435.2037.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((3-phenylureido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(107)

A flask containing a solution of the crude amine 33 (originating from0.54 mmol of azide 26) in 5 mL of pyridine was purged with nitrogen gasand treated with phenylisocyanate (0.065 mL, 0.59 mmol). After 3 h TLC(CH₂Cl₂/MeOH 97:3) showed complete conversion of the starting material.Purification via flash column chromatography (CH₂Cl₂/MeOH 98:2) affordedthe final compound in 76.3% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.32(s, 3 H) 1.49 (s, 3 H) 3.14 (app. dt, J=14.2, 4.5 Hz, 1 H) 3.62 (app.dt, J=14.3, 7.1 Hz, 1 H) 3.74 (dd, J=14.4, 5.6 Hz, 1 H) 3.81 (app. s, 2H) 3.93 (dd, J=14.4, 7.3 Hz, 1 H) 4.11 (app. t, J=5.13 Hz, 1 H) 4.51 (d,J=1.2 Hz, 1 H) 6.39 (dd, J=7.2, 4.83 Hz, 1 H) 6.96 (app. t, J=7.3 Hz, 1H) 7.21 (app. t, J=7.9 Hz, 2 H) 7.30-7.44 (m, 4 H) 7.46-7.54 (m, 1 H)7.78 (t, J=6.3 Hz, 1 H) 7.85-7.95 (m, 2 H) 8.06 (s, 1 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.4, 27.9, 40.1, 42.6, 75.0, 84.0, 84.4, 92.0, 113.5,119.6, 122.6, 127.3, 128.7, 128.9, 132.0, 133.5, 139.3, 156.8, 168.6.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₈N₃O₅ ⁺ 426.20235; Found426.2041.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((3-phenylthioureido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-34)methyl)benzamide(108)

A flask containing a solution of the crude amine 33 (originating from0.56 mmol of azide 26) in 5 mL of pyridine was purged with nitrogen gasand treated with phenylisothiocyanate (0.074 mL, 0.62 mmol). After 3 hTLC (CH₂Cl₂/MeOH 97:3) showed no starting material. Purification viaflash column chromatography (CH₂Cl₂/MeOH 95:5) afforded the finalcompound in 65.2% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s, 3 H)1.48 (s, 3 H) 3.63-3.80 (m, 3 H) 3.83 (app. s, 2 H) 3.97-4.07 (m, 1 H)4.30 (app. t, J=6.0 Hz, 1 H) 4.48 (d, J=1.8 Hz, 1 H) 6.84 (br. s., 1 H)7.09 (br. s., 1 H) 7.16-7.53 (m, 8 H) 7.70-7.83 (m, 2 H) 8.61 (br. s., 1H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 43.1, 45.1, 75.0, 83.3,84.4, 92.1, 113.8, 124.8, 126.6, 127.1, 128.6, 129.7, 131.9, 133.5,136.9, 168.2, 181.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₈N₃O₄S⁺442.17950; Found 442.1802.

N-(((3aS,6R,6aR)-6-(Acetamidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(109)

A solution of the crude amine 33 in CH₂Cl₂ (24 mL per mmol) was treatedwith diisopropylethylamine (2 eq.) and acetic anhydride (1.2 eq.). Thereaction mixture was cooled in an ice-bath and stirred overnight. It wasevaporated under reduced pressure, the residue was diluted with EtOAcand washed with 0.1 M aq. HCl and sat. aq. NaHCO₃. The organic layer wasdried over sodium sulphate, filtered and concentrated. The residue waspurified by column chromatography (CH₂Cl₂/MeOH 100:0→90:10) to affordthe title compound as a white foam in 96.2% yield. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.37 (s, 3 H) 1.51 (s, 3 H) 2.03 (s, 3 H) 3.18 (ddd,J=14.1, 5.9, 4.9 Hz, 1 H) 3.57-3.69 (m, 2 H) 3.86 (app. s, 2 H) 3.95(dd, J=14.2, 7.2 Hz, 1 H) 4.14 (app. td, J=6.3, 1.5 Hz, 1 H) 4.43 (d,J=1.5 Hz, 1 H) 7.02 (dd, J=7.0, 4.7 Hz, 1 H) 7.38-7.56 (m, 4 H)7.83-7.91 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 23.1, 27.7, 27.8,39.4, 42.9, 74.8, 83.8, 84.8, 92.1, 113.5, 127.2, 128.6, 131.9, 133.7,168.2, 171.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₅N₂O₅ ⁺349.17580; Found 349.1756.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-(pivalamidomethyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(110)

A cooled (0° C.) solution of the crude amine 33 in CH₂Cl₂ (20 mL permmol) was treated with triethylamine (2 eq.) and pivaloyl chloride (1.1eq.). The reaction mixture was stirred overnight and concentrated underreduced pressure. The residue was diluted with EtOAc and washed with 0.1M aqueous hydrochloric acid and saturated sodium bicarbonate solution.The organic layer was dried over sodium sulphate, filtered andconcentrated. The product was purified by column chromatography(toluene/EtOAc 100:0→20:80) and appeared as a white foam 74.10% yield.¹H NMR (300 MHz, CDCl₃) δ ppm 1.22 (s, 9 H) 1.38 (s, 3 H) 1.52 (s, 3 H)3.24 (ddd, J=13.9, 7.3, 5.1 Hz, 1 H) 3.53 (app. dt, J=14.2, 7.3 Hz, 1 H)3.76 (dd, J=14.4, 5.9 Hz, 1 H) 3.84-3.95 (m, 3 H) 4.15 (app. td, J=7.3,1.2 Hz, 1 H) 4.40 (d, J=1.2 Hz, 1 H) 6.30 (t, J=5.9 Hz, 1 H) 7.33 (t,J=6.2 Hz, 1 H) 7.39-7.55 (m, 3 H) 7.84-7.92 (m, 2 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.6, 27.77, 27.82, 38.9, 39.4, 43.3, 74.9, 83.8, 85.1,92.2, 113.5, 127.3, 128.7, 131.9, 133.8, 167.9, 179.4. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₁H₃₁N₂O₅ ⁺ 391.22275; Found 391.2242.

N-(((3aS,6R,6aR)-6-((5-chloro-1,3-dioxoisoindolin-2-yl)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(111)

To a solution of the crude amine 33 (0.32 g, 1.04 mmol) in 10 mL ofCHCl₃ was added 4-chlorophthalic anhydride (0.26 g, 1.40 mmol) and thereaction mixture was heated to reflux overnight. TLC analysis(toluene/EtOAc 3:2) showed consumption of starting material. Thereaction mixture was concentrated under reduced pressure. The residuewas taken up in EtOAc and washed with saturated sodium bicarbonatesolution. The organic layer was dried over sodium sulphate, filtered andconcentrated. Purification via flash column chromatography(toluene/EtOAc 100:0→60:40) afforded the title compound as a foam in21.9% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.42 (s, 3 H) 1.50 (s, 3 H)3.67 (dd, J=14.1, 5.9 Hz, 1 H) 3.78 (dd, J=14.4, 5.6 Hz, 1 H) 3.86 (dd,J=14.1, 9.7 Hz, 1 H) 3.93-4.04 (m, 3 H) 4.41 (app. dd, J=9.7, 5.9 Hz, 1H) 4.48 (d, J=0.6, 1 H) 6.83 (t, J=6.0 Hz, 1 H) 7.41-7.55 (m, 3 H)7.64-7.70 (m, 1 H) 7.73-7.90 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.6, 28.2, 37.5, 43.4, 74.9, 82.3, 85.5, 92.7, 113.7, 124.0, 124.7,127.1, 128.8, 130.1, 131.9, 133.7, 133.9, 134.2, 140.9, 166.9, 167.2,167.8. HRMS (ESI-TOF) [M+H]⁺ Calcd for C₂₄H₂₄ClN₂O₆ ⁺ 471.13174; Found471.1324.

N-(((3aS,6R,6aR)-6-((benzylamino)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(112)

A flask containing a solution of crude amine 33 (originating from 0.60mmol of azide 26) in MeOH (9 mL) was purged with nitrogen gas. Molecularsieves (3 Å, rods) were added and the flask was flushed again.Benzaldehyde (0.18 mL, 1.8 mmol) was added and the whole was stirred for4 h at RT. After that, the aldimine was carefully treated with NaBH₄(0.11 g, 3.0 mmol) for 30 minutes. The RM was filtered and the filtratewas adsorbed onto celite. The product was purified by columnchromatography (toluene/EtOAc 100:0→60:40) and appeared as a pale yellowoil (47.3%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (s, 3 H) 1.54 (s, 3 H)2.04 (br. s., 1 H) 2.71-2.79 (m, 2 H) 3.71-3.92 (m, 6 H) 4.20 (app. td,J=6.1, 1.9 Hz, 1 H) 4.36 (d, J=2.1 Hz, 1 H) 6.76 (t, J=5.7 Hz, 1 H)7.19-7.35 (m, 5 H) 7.39-7.54 (m, 3 H) 7.75-7.81 (m, 2 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.9, 28.0, 43.9, 49.4, 53.8, 75.3, 84.9, 86.2, 91.9,113.9, 127.0, 127.1, 128.2, 128.5, 128.7, 131.8, 134.2, 139.9, 167.8.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₃N₂O₄ ⁺ 397.21218; Found397.2119.

N-(((3aS,6R,6aR)-6-(benzamidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-N-methylbenzamide(113)

Azide 32 was subjected to general procedure 3, followed by generalprocedure 4 to obtain the title compound as a white foam (94.3%)¹H NMR(300 MHz, CDCl₃) δ ppm 1.43 (s, 3 H) 1.53 (s, 3 H) 3.15 (s, 3 H)3.67-3.79 (m, 3 H) 3.89-3.99 (m, 2 H) 4.04 (d, J=14.4 Hz, 1 H) 4.40(app. t, J=6.4 Hz, 1 H) 4.61 (app. s, 1 H) 7.33-7.46 (m, 9 H) 7.87 (app.d, J=7.3 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.9, 39.8, 40.7,51.5, 75.6, 83.5, 84.9, 93.4, 113.3, 126.8, 127.3, 128.4, 128.6, 129.9,131.4, 134.2, 135.8, 167.6, 172.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₄H₂₃N₂O₅ ⁺ 425.20710; Found 425.2067.

N-(((3aS,6R,6aR)-2,2-dimethyl-6-((1-oxoisoindolin-2-yl)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide(114)

To a flask containing a solution of the crude amine 33 (originating from0.46 mmol of azide 26) in 6 mL of MeOH was added TEA (70.9 μL, 0.51mmol) and methyl 2-(bromomethyl)benzoate (269) (0.12 g, 0.51 mmol). Themixture was heated to reflux at 80° C. for 14 h. The reaction wasmonitored by mass spectrometry (ESI-TOF), which indicated the formationof the target compound. The reaction mixture was concentrated andadsorbed onto celite. Purification via flash column chromatography(toluene/EtOAc 100:0→30:70) yielded the title compound as a white foam(58.8%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (s, 3 H) 1.51 (s, 3 H) 3.46(dd, J=14.4, 7.0 Hz, 1 H) 3.77 (dd, J=14.1, 5.6 Hz, 1 H) 3.85-4.05 (m, 4H) 4.34 (app. t., J=7.5, 1 H) 4.42 (d, J=17.0 Hz, 1 H) 4.57 (d, J=17.0Hz, 1 H) 4.61 (d, J=1.2 Hz, 1 H) 7.37-7.58 (m, 6 H) 7.66 (t, J=6.2 Hz, 1H) 7.81-7.87 (m, 1 H) 7.91-8.04 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.7, 27.8, 42.5, 43.1, 51.2, 74.8, 83.4, 85.7, 92.3, 113.5, 122.9,123.8, 127.4, 128.3, 128.6, 131.7, 131.8, 132.1, 133.9, 141.5, 167.8,169.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₇N₂O₅ ⁺ 423.19145;Found 423.1908.

N-(((3aR,4R,6aS)-6a-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(115)

General procedure 6. White foam, 45.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.29 (s, 3 H) 1.49 (s, 3 H) 3.46 (ddd, J=14.0, 8.7, 4.3 Hz, 1 H) 3.85(ddd, J=14.0, 7.3, 5.1 Hz, 1 H) 3.95 (d, J=10.5 Hz, 1 H) 3.98-4.06 (m, 3H) 4.27 (ddd, J=8.6, 5.1, 1.8 Hz, 1 H) 4.59 (d, J=1.8 Hz, 1 H) 6.59 (dd,J=6.4, 4.4 Hz, 1 H) 7.39-7.53 (m, 3 H) 7.71-7.92 (m, 6 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 27.7, 27.9, 39.9, 41.7, 75.2, 83.9, 86.0, 91.8, 114.6,123.7, 127.2, 128.7, 131.7, 131.9, 134.3, 134.5, 167.7, 168.5. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₅N₂O₆ ⁺ 437.17071, found 437.1712.

2-chloro-N-(((3aR,4R,6aS)-6a-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(116)

General procedure 6. White foam, 57.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.29 (s, 3 H) 1.49 (s, 3 H) 3.46 (ddd, J=14.0, 9.0, 4.3 Hz, 1 H) 3.84(ddd, J=14.1, 7.0, 5.3 Hz, 1 H) 3.94 (d, J=10.5 Hz, 1 H) 3.98-4.12 (m, 3H) 4.26 (ddd, J=8.8, 5.3, 1.8 Hz, 1 H) 4.59 (d, J=1.8 Hz, 1 H) 6.65 (dd,J=6.2, 4.7 Hz, 1 H) 7.27-7.42 (m, 3 H) 7.63-7.69 (m, 1 H) 7.70-7.79 (m,2 H) 7.81-7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 40.0,41.7, 75.1, 83.7, 86.0, 91.8, 114.5, 123.7, 127.1, 130.2, 130.3, 130.8,131.4, 131.8, 134.4, 134.9, 166.8, 168.5. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₄ClN₂O₆ ⁺ 471.13174, found 471.1313.

N-(((3aR,4R,6aS)-6a-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(117)

General procedure 7. Transparent oil, 95.8% ¹H NMR (300 MHz, CDCl₃) δppm 1.42 (s, 3 H) 1.51-1.70 (m, 5 H) 2.98 (s, 2 H) 3.46 (ddd, J=14.1,7.9, 4.4 Hz, 1 H) 3.76 (ddd, J=14.1, 6.4, 5.3 Hz, 1 H) 3.90 (d, J=10.0Hz, 1 H) 3.95 (d, J=10.3 Hz, 1 H) 4.26 (ddd, J=7.7, 5.5, 1.8 Hz, 1 H)4.39 (d, J=2.1 Hz, 1 H) 6.67 (br. s., 1 H) 7.39-7.54 (m, 3 H) 7.75-7.81(m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 28.0, 28.1, 40.3, 46.6, 75.5,84.2, 85.4, 93.3, 113.9, 127.1, 128.7, 131.8, 134.4, 167.9. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₆H₂₃N₂O₄ ⁺ 307.16523, found 307.1658.

N-(((3aR,4R,6aS)-6a-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2-chlorobenzamide(118)

General procedure 7. Transparent oil, 71.9% ¹H NMR (300 MHz, CDCl₃) δppm 1.29-1.46 (m, 5 H) 1.54 (s, 3 H) 2.99 (s, 2 H) 3.47 (ddd, J=13.9,7.8, 4.5 Hz, 1 H) 3.78 (ddd, J=14.0, 6.5, 5.1 Hz, 1 H) 3.90 (d, J=10.3Hz, 1 H) 3.94 (d, J=10.0 Hz, 1 H) 4.27 (ddd, J=7.5, 5.2, 1.9 Hz, 1 H)4.41 (d, J=1.8 Hz, 1 H) 6.86 (br. s, 1 H) 7.32-7.43 (m, 3 H) 7.62-7.66(m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.9, 28.1, 40.4, 46.7, 75.5,83.9, 85.5, 93.3, 113.9, 127.2, 130.2, 130.4, 130.8, 131.5, 135.1,167.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₆H₂₂ClN₂O₄ ⁺ 341.12626,found 341.1269.

2-chloro-N-(((3aR,4R,6aS)-2,2-dimethyl-6a-((4-methylbenzamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(119)

General procedure 4. White foam, 91.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 2.37 (s, 3 H) 3.39 (ddd, J=13.9, 7.3, 4.8Hz, 1 H) 3.64-3.80 (m, 2 H) 3.83-3.96 (m, 3 H) 4.25 (app. td, J=7.1, 1.3Hz, 1 H) 4.51 (d, J=1.5 Hz, 1 H) 7.09-7.39 (m, 7 H) 7.54-7.59 (m, 1 H)7.68-7.76 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 21.5, 27.7, 27.8,39.8, 43.1, 74.9, 83.6, 85.1, 92.2, 113.5, 127.0, 127.2, 129.3, 129.7,130.2, 130.8, 130.9, 131.3, 135.1, 142.3, 167.5, 167.9. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₄H₂₈ClN₂O₅ ⁺ 459.16813, found 459.1682.

2-chloro-N-(((3aR,4R,6aS)-6a-((4-fluorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(120)

General procedure 4. White foam, 98.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.36 (ddd, J=13.9, 7.2, 5.0 Hz, 1 H)3.66-3.82 (m, 2 H) 3.85-3.97 (m, 3 H) 4.24 (app. td, J=7.3, 1.0 Hz, 1 H)4.52 (d, J=1.5 Hz, 1 H) 7.00-7.14 (m, 3 H) 7.28-7.41 (m, 4 H) 7.54-7.61(m, 1 H) 7.82-7.91 (m, 2 H). ¹³F NMR (282 MHz, CDCl₃) δ ppm −107.8 (m).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.76, 27.81, 39.8, 43.3, 74.9, 83.7,85.3, 92.2, 113.6, 115.7 (d, J=21.9 Hz), 127.1, 129.7 (d, J=9.2 Hz),129.8, 129.9 (d, J=3.5 Hz), 130.3, 130.9, 131.5, 135.0, 165.0 (d,J=252.2 Hz), 166.9, 167.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₃H₂₅ClFN₂O₅ ⁺ 463.14305, found 463.1425.

2-chloro-N-(((3aR,4R,6aS)-6a-((4-chlorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(121)

General procedure 4. White foam, 97.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 3.34 (ddd, J=14.1, 7.2, 4.8 Hz, 1 H)3.65-3.80 (m, 2 H) 3.84-3.96 (m, 3 H) 4.23 (app. td, J=7.3, 1.2 Hz, 1 H)4.53 (d, J=1.5 Hz, 1 H) 7.08 (dd, J=7.2, 4.8 Hz, 1 H) 7.28-7.41 (m, 5 H)7.46 (t, J=6.2 Hz, 1 H) 7.53-7.58 (m, 1 H) 7.76-7.81 (m, 2 H). ¹³C NMR(75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.8, 43.2, 74.8, 83.7, 85.2, 92.1,113.6, 127.1, 128.7, 128.9, 129.7, 130.3, 130.8, 131.5, 132.1, 134.9,138.0, 166.9, 167.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₅Cl₂N₂O₅⁺ 479.11350, found 479.1132.

2-chloro-N-(((3aR,4R,6aS)-6a-((4-methoxybenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(122)

General procedure 4. White foam, 92.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.51 (s, 3 H) 3.37 (ddd, J=13.9, 7.2, 4.8 Hz, 1 H)3.61-3.80 (m, 2 H) 3.82 (s, 3 H) 3.86-3.96 (m, 3 H) 4.24 (app. td,J=7.2, 0.9 Hz, 1 H) 4.52 (d, J=1.5 Hz, 1 H) 6.85-6.92 (m, 2 H) 7.17 (dd,J=6.9, 5.1 Hz, 1 H) 7.24-7.38 (m, 4 H) 7.53-7.59 (m, 1 H) 7.73-7.85 (m,2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.8, 43.1, 55.4, 74.9,83.6, 85.1, 92.2, 113.4, 113.8, 125.9, 127.0, 129.0, 129.6, 130.2,130.8, 131.3, 135.1, 162.4, 167.4, 167.5. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₈ClN₂O₆ ⁺ 475.16304, found 475.1636.

2-chloro-N-(((3aR,4R,6aS)-6a-((4-cyanobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(123)

General procedure 4. White foam, 94.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.31 (ddd, J=14.0, 7.1, 4.7 Hz, 1 H)3.69-3.81 (m, 2 H) 3.85-3.99 (m, 3 H) 4.19-4.27 (m, 1 H) 4.55 (d, J=1.2Hz, 1 H) 7.05 (dd, J=7.5, 4.5 Hz, 1 H) 7.26-7.40 (m, 3 H) 7.52-7.58 (m,1 H) 7.65-7.71 (m, 2 H) 7.75 (t, J=6.3 Hz, 1 H) 7.94-8.02 (m, 2 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.70, 27.73, 39.7, 43.3, 74.7, 83.7, 85.3,92.0, 113.6, 115.2, 118.1, 127.1, 128.1, 129.6, 130.4, 130.8, 131.6,132.4, 134.8, 137.7, 166.2, 167.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₄H₂₅ClN₃O₅ ⁺ 470.14773, found 470.1478.

2-chloro-N-(((3aR,4R,6aS)-6a-((4-(dimethylamino)benzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(124)

General procedure 4. White foam, 83.6% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.51 (s, 3 H) 2.99 (s, 6 H) 3.41 (ddd, J=13.8, 7.3, 5.0Hz, 1 H) 3.61 (dd, J=14.4, 5.3 Hz, 1 H) 3.69-3.79 (m, 1 H) 3.86-3.96 (m,3 H) 4.26 (app. td, J=7.2, 1.0 Hz, 1 H) 4.51 (d, J=1.5 Hz, 1 H) 6.62 (m,2 H) 7.04 (t, J=6.2 Hz, 1 H) 7.20 (dd, J=6.7, 5.3 Hz, 1 H) 7.23-7.38 (m,3 H) 7.52-7.61 (m, 1 H) 7.66-7.77 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δppm 27.7, 27.8, 39.8, 40.1, 42.9, 74.9, 83.4, 85.0, 92.4, 111.0, 113.3,120.2, 126.9, 128.7, 129.7, 130.2, 130.9, 131.2, 135.2, 152.6, 167.4,167.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₅H₃₁ ClN₃O₅ ⁺ 488.19468,found 488.1947.

2-chloro-N-(((3aR,4R,6aS)-2,2-dimethyl-6a-((4-(trifluoromethyl)benzamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(125)

General procedure 4. White foam, 74.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.35 (ddd, J=13.9, 7.2, 4.7 Hz, 1 H)3.68-3.82 (m, 2 H) 3.85-4.00 (m, 3 H) 4.24 (app. td, J=7.3, 0.9 Hz, 1 H)4.56 (d, J=1.5 Hz, 1 H) 7.12 (dd, J=7.2, 4.8 Hz, 1 H) 7.24-7.39 (m, 3 H)7.49-7.58 (m, 1 H) 7.61-7.73 (m, 3 H) 7.96 (app. d, J=7.9 Hz, 2 H). ¹⁹FNMR (282 MHz, CDCl₃) δ ppm −63.0 (s). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.7, 27.8, 39.8, 43.3, 74.8, 83.7, 85.3, 92.1, 113.6, 123.7 (q, J=274.9Hz), 125.6 (q, J=3.8 Hz), 127.1, 127.8, 129.6, 130.3, 130.8, 131.5,133.4 (q, J=32.0 Hz), 134.9, 137.0, 166.8, 167.8. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₄H₂₅ClF₃N₂O₅ ⁺ 513.13986, found 513.1384.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)isonicotinamide(126)

General procedure 4. White foam, 83.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.33 (ddd, J=13.9, 7.0, 4.8 Hz, 1 H)3.70-3.81 (m, 2 H) 3.86-4.00 (m, 3 H) 4.20-4.28 (m, 1 H) 4.56 (d, J=1.2Hz, 1 H) 7.21 (dd, J=7.3, 5.0 Hz, 1 H) 7.29-7.42 (m, 3 H) 7.53-7.59 (m,1 H) 7.69-7.74 (m, 2 H) 7.86 (t, J=6.3 Hz, 1 H) 8.63-8.70 (m, 2 H). ¹³CNMR (75 MHz, CDCl₃) δ ppm 27.70, 27.75, 39.8, 43.2, 74.8, 83.8, 85.3,92.0, 113.6, 121.2, 127.1, 129.6, 130.4, 130.8, 131.6, 134.8, 141.0,150.5, 166.1, 167.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₅ClN₃O₅ ⁺446.14773 found 446.1475.

2-chloro-N-(((3aR,4R,6aS)-6a-((3-fluorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(127)

General procedure 4. White foam, 82.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.30-3.41 (m, 1 H) 3.65-3.83 (m, 2 H)3.83-3.96 (m, 3 H) 4.24 (app. t, J=7.2 Hz, 1 H) 4.53 (d, J=1.5 Hz, 1 H)7.06-7.65 (m, 10 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm −111.7 (m). ¹³C NMR(75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.8, 43.3, 74.8, 83.6, 85.2, 92.1,113.6, 114.7 (d, J=23.0 Hz), 118.8 (d, J=21.9 Hz), 122.7 (d, J=3.5 Hz),127.1, 129.7, 130.285, 130.293 (d, J=8.1 Hz), 130.8, 131.4, 134.9, 136.0(d, J=6.9 Hz), 162.8 (d, J=247.6 Hz), 166.7 (app. s), 167.6. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₅ClFN₂O₅ ⁺ 463.14305, found463.1438.

2-chloro-N-(((3aR,4R,6aS)-6a-((3-chlorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(128)

General procedure 4. White foam, 85.7% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.38 (ddd, J=14.0, 7.3, 4.8 Hz, 1 H)3.69-3.82 (m, 2 H) 3.84-3.95 (m, 3 H) 4.25 (app. td, J=7.2, 0.9 Hz, 1 H)4.52 (d, J=1.2 Hz, 1 H) 7.06 (dd, J=7.0, 5.0 Hz, 1 H) 7.27-7.49 (m, 6 H)7.56-7.61 (m, 1 H) 7.71 (app. dt, J=7.9, 1.3 Hz, 1 H) 7.84 (app. t,J=1.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.76, 27.81, 39.9, 43.4,74.9, 83.7, 85.2, 92.1, 113.7, 125.3, 127.1, 127.7, 129.8, 130.0, 130.3,130.8, 131.6, 131.9, 134.8, 134.9, 135.5, 166.8, 167.7. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₃H₂₅Cl₂N₂O₅ ⁺ 479.11350, found 479.1144.

2-chloro-N-(((3aR,4R,6aS)-2,2-dimethyl-6a-((3-(trifluoromethyl)benzamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(129)

General procedure 4. White foam, 97.2% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.34 (ddd, J=14.1, 7.0, 4.7 Hz, 1 H)3.67-3.83 (m, 2 H) 3.87-4.02 (m, 3 H) 4.25 (app. td, J=7.3, 0.9 Hz, 1 H)4.56 (d, J=1.2 Hz, 1 H) 7.04 (dd, J=7.3, 5.0 Hz, 1 H) 7.28-7.40 (m, 3 H)7.51-7.60 (m, 2 H) 7.65 (t, J=6.2 Hz, 1 H) 7.72-7.77 (m, 1 H) 8.05 (app.d, J=7.9 Hz, 1 H) 8.16 (app. s, 1 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm−62.7 (s). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.8, 43.3, 74.8,83.7, 85.3, 92.1, 113.6, 123.8 (q, J=272.5 Hz), 124.5 (q, J=3.8 Hz),127.1, 128.4 (q, J=3.5 Hz), 129.3, 129.8, 130.3, 130.6, 130.8, 131.1 (q,J=33.0 Hz), 131.6, 134.6, 134.8, 166.6, 167.7. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₄H₂₅ClF₃N₂O₅ ⁺ 513.13986, found 513.1387.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)nicotinamide(130)

General procedure 4. White foam, 79.9% ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 3 H) 1.52 (s, 3 H) 3.35 (ddd, J=13.9, 7.2, 4.7 Hz, 1 H)3.67-3.81 (m, 2 H) 3.87-4.01 (m, 3 H) 4.24 (app. td, J=7.3, 1.2 Hz, 1 H)4.55 (d, J=1.5 Hz, 1 H) 7.20-7.40 (m, 5 H) 7.53-7.59 (m, 1 H) 7.79 (t,J=6.2 Hz, 1 H) 8.18 (ddd, J=8.0, 2.2, 1.8 Hz, 1 H) 8.66 (app. dd, J=5.0,1.8 Hz, 1 H) 9.06 (dd, J=2.2, 0.7 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δppm 27.75 (2 C), 39.7, 43.2, 74.8, 83.7, 85.3, 92.0, 113.6, 123.5,127.1, 129.5, 129.7, 130.3, 130.8, 131.5, 134.9, 135.3, 148.5, 152.3,166.2, 167.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₅ClN₃O₅ ⁺446.14773, found 446.1470.

2-chloro-N-(((3aR,4R,6aS)-2,2-dimethyl-6a-((2-methylbenzamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(131)

General procedure 4. White foam, 81.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 2.39 (s, 3 H) 3.43 (ddd, J=14.0, 7.7, 4.7Hz, 1H) 3.68-3.85 (m, 3 H) 3.92 (app. s, 2 H) 4.27 (ddd, J=7.7, 6.1, 1.8Hz, 1 H) 4.47 (d, J=1.8 Hz, 1 H) 6.61 (t, J=6.2 Hz, 1 H) 6.93 (dd,J=6.7, 5.0 Hz, 1 H) 7.14-7.39 (m, 7 H) 7.54-7.59 (m, 1 H). ¹³C NMR (75MHz, CDCl₃) δ ppm 19.9, 27.87, 27.93, 39.9, 43.5, 75.1, 83.7, 85.3,92.2, 113.8, 125.9, 126.7, 127.0, 129.9, 130.25 (2C), 130.8, 131.2,131.3, 135.1, 135.7, 136.3, 167.2, 170.6. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₈ClN₂O₅ ⁺ 459.16813, found 459.1676.

2-chloro-N-(((3aR,4R,6aS)-6a-((2-fluorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(132)

General procedure 4. White foam, 68.1% ¹H NMR (300 MHz, CDCl₃) δ ppm1.41 (s, 3 H) 1.54 (s, 3 H) 3.50 (ddd, J=14.0, 8.0, 4.8 Hz, 1 H)3.67-3.84 (m, 2 H) 3.86-3.99 (m, 3 H) 4.31 (ddd, J=7.7, 5.9, 1.3 Hz, 1H) 4.42 (d, J=1.5 Hz, 1 H) 6.92 (t, J=5.6 Hz, 1 H) 7.12 (app. dd,J=12.2, 8.3 Hz, 1 H) 7.20-7.40 (m, 5 H) 7.43-7.53 (m, 1 H) 7.57-7.64 (m,1 H) 8.01 (app. td, J=7.9, 1.8 Hz, 1 H). ¹⁹F NMR (282 MHz, CDCl₃) δ ppm−113.2 (m). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 40.1, 43.4, 75.1,83.6, 84.9, 92.1, 113.9, 116.2 (d, J=24.2 Hz), 120.5 (d, J=11.5 Hz),124.9 (d, J=3.5 Hz), 127.0, 130.1 (d, J=17.3 Hz), 130.2, 130.8, 131.2,132.1, 133.7 (d, J=9.2 Hz), 135.2, 160.7 (d, J=248.8 Hz), 164.0 (d,J=3.5 Hz), 167.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₅ClFN₂O₅ ⁺463.14305, found 463.1428.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)furan-2-carboxamide(133)

General procedure 4. White foam, 87.3% ¹H NMR (300 MHz, CDCl₃) δ ppm1.41 (s, 3 H) 1.53 (s, 3 H) 3.46 (ddd, J=14.1, 7.9, 5.0 Hz, 1 H) 3.67(dd, J=14.4, 5.9 Hz, 1 H) 3.72-3.94 (m, 4 H) 4.28 (ddd, J=7.8, 6.2, 1.6Hz, 1 H) 4.42 (d, J=1.5 Hz, 1 H) 6.49 (dd, J=3.4, 1.9 Hz, 1 H) 6.91 (dd,J=6.2, 5.3 Hz, 1 H) 7.03 (t, J=6.2 Hz, 1 H) 7.11 (dd, J=3.5, 0.6 Hz, 1H) 7.26-7.40 (m, 3 H) 7.45 (dd, J=1.8, 0.9 Hz, 1 H) 7.58-7.63 (m, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.9, 40.0, 42.5, 75.0, 83.6, 85.1,92.2, 112.3, 114.0, 114.9, 127.0, 129.9, 130.3, 130.8, 131.3, 135.1,144.5, 147.5, 158.8, 167.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₄ClN₂O₆ ⁺ 435.13174, found 435.1323.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)furan-3-carboxamide(134)

General procedure 4. White foam, 88.5% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.51 (s, 3 H) 3.30 (ddd, J=13.9, 6.7, 4.8 Hz, 1 H) 3.55(dd, J=14.2, 5.1 Hz, 1 H) 3.74-4.01 (m, 4 H) 4.19-4.26 (m, 1 H) 4.53 (d,J=1.2 Hz, 1 H) 6.76 (dd, J=1.8, 0.9 Hz, 1 H) 7.10 (dd, J=7.3, 4.7 Hz, 1H) 7.28-7.42 (m, 5 H) 7.56-7.62 (m, 1 H) 8.03 (dd, J=1.5, 0.9 Hz, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.7, 39.7, 42.3, 74.7, 83.8, 85.4,92.1, 108.6, 113.4, 122.1, 127.1, 129.7, 130.4, 130.9, 131.6, 134.8,143.8, 145.5, 163.3, 167.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₄ClN₂O₆ ⁺ 435.13174, found 435.1309.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)pyrimidine-5-carboxamide(135)

General procedure 4. White foam, 75.4% ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (s, 3 H) 1.52 (s, 3 H) 3.30 (ddd, J=14.0, 6.8, 4.7 Hz, 1 H)3.67-3.83 (m, 2 H) 3.86-4.08 (m, 3 H) 4.23 (app. t, J=7.5 Hz, 1 H) 4.58(app. s, 1 H) 7.09 (dd, J=7.3, 5.0 Hz, 1 H) 7.28-7.42 (m, 3 H) 7.55-7.63(m, 1 H) 8.07 (t, J=6.2 Hz, 1 H) 9.22 (app. s, 2 H) 9.27 (app. s, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.70, 27.75, 39.7, 43.1, 74.7, 83.8,85.4, 91.8, 113.6, 127.2, 127.4, 129.8, 130.4, 130.8, 131.8, 134.5,156.2, 160.6, 164.2, 168.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₄ClN₄O₅ ⁺ 447.14297, found 447.1439.

N,N′-(((3aS,6R,6aR)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(2-chlorobenzamide)(136)

Azide 27 was subjected to general procedure 3, followed by generalprocedure 4. White powder, 76.3% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.39 (s,3 H) 1.52 (s, 3 H) 3.42 (ddd, J=14.1, 7.8, 4.8 Hz, 1 H) 3.70-3.88 (m, 3H) 3.94 (s, 2 H) 4.26 (ddd, J=7.8, 6.3, 1.5 Hz, 1 H) 4.47 (d, J=1.8 Hz,1 H) 6.91 (dd, J=6.7, 5.0 Hz, 1 H) 7.05 (t, J=6.0 Hz, 1 H) 7.23-7.41 (m,6 H) 7.52-7.58 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.85 (2C), 39.9,43.7, 75.0, 83.7, 85.3, 92.0, 113.8, 127.0, 127.1, 129.7, 129.8, 130.2,130.3, 130.7, 130.8, 131.3, 131.4, 134.9, 135.0, 167.2, 167.3. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₃H₂₅Cl₂N₂O₅ ⁺ 479.11350; Found479.1144.

N-(((3aR,4R,6aS)-6a-((2-chlorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(137)

Azide 27 was subjected to general procedure 3, followed by generalprocedure 4. White powder, 70.5% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (s,3 H) 1.51 (s, 3 H) 3.52 (ddd, J=14.0, 7.3, 5.1 Hz, 1 H) 3.71-3.90 (m, 3H) 3.92-4.01 (m, 2 H) 4.28-4.36 (app. td, J=6.9, 7.0 Hz, 1 H) 4.51 (d,J=1.5 Hz, 1 H) 7.15 (t, J=6.2 Hz, 1 H) 7.21 (t, J=5.9 Hz, 1 H) 7.26-7.47(m, 6 H) 7.55-7.63 (m, 5 H) 7.84-7.92 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃)δ ppm 27.85 (2C), 39.9, 43.7, 75.1, 83.8, 85.2, 92.1, 113.8, 127.17,127.23, 127.8, 128.0, 128.94 (2C), 129.7, 130.4, 130.8, 131.5, 132.6,134.9, 140.0, 144.3, 167.61, 167.64. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcdfor C₂₉H₃₀ClN₂O₅ ⁺ 521.18378; Found 521.1831.

N-(((3aR,4R,6aS)-6a-((2-chlorobenzamido)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyridazine-4-carboxamide(138)

Azide 27 was subjected to general procedure 3, followed by generalprocedure 4. White powder, 75.4% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s,3 H) 1.50 (s, 3 H) 3.48-3.59 (m, 1 H) 3.66-3.94 (m, 5 H) 4.32 (app. td,J=6.3, 1.5 Hz, 1 H) 4.49 (d, J=1.5 Hz, 1 H) 7.27-7.44 (m, 4 H) 7.54-7.60(m, 1 H) 7.99 (dd, J=5.3, 2.3 Hz, 1 H) 8.53 (t, J=6.0 Hz, 1 H) 9.26 (dd,J=5.3, 1.2 Hz, 1 H) 9.64 (dd, J=2.3, 1.2 Hz, 1 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.8, 27.9, 40.2, 43.5, 75.1, 83.3, 84.7, 92.0, 113.9,124.4, 127.2, 129.4, 130.4, 130.7, 131.6, 131.7, 134.6, 149.1, 151.8,164.1, 168.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₄ClN₄O₅ ⁺447.14297; Found 447.1422.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(139)

Azide 28 was subjected to general procedure 3, followed by generalprocedure 4. White powder, 59.8% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.40 (s,3 H) 1.53 (s, 3 H) 3.41 (ddd, J=13.9, 7.3, 4.8 Hz, 1 H) 3.67-3.85 (m, 2H) 3.88-4.00 (m, 3 H) 4.27 (app. td, J=7.2, 1.2 Hz, 1H) 4.54 (d, J=1.5Hz, 1 H) 7.03 (dd, J=6.9, 4.8 Hz, 1 H) 7.26-7.49 (m, 7 H) 7.55-7.65 (m,5 H) 7.88-7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 39.9,43.3, 74.9, 83.7, 85.3, 92.2, 113.6, 127.1, 127.2, 127.3, 127.8, 128.1,129.0, 129.8, 130.3, 130.9, 131.4, 132.4, 135.0, 140.0, 144.6, 167.5,167.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₉H₃₀ClN₂O₅ ⁺ 521.18378;Found 521.1825.

N-(((3aR,4R,6aS)-6a-([1,1′-biphenyl]-4-carboxamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)pyridazine-4-carboxamide(140)

Azide 28 was subjected to general procedure 3, followed by generalprocedure 4. White powder, 58.0% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (s,3 H) 1.52 (s, 3 H) 3.52-3.64 (m, 2 H) 3.85-4.04 (m, 4 H) 4.35 (app. t,J=5.1 Hz, 1 H) 4.50 (d, J=1.8 Hz, 1 H) 7.33-7.50 (m, 4 H) 7.55-7.72 (m,4 H) 7.92 (d, J=8.5 Hz, 2 H) 8.07 (dd, J=5.3, 2.1 Hz, 1 H) 8.56-8.67 (m,1 H) 9.32 (app. d, J=5.0 Hz, 1 H) 9.77 (app. s, 1 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 27.7, 28.1, 40.3, 43.0, 75.2, 83.1, 84.3, 92.3, 113.9,124.5, 127.3, 127.52, 127.53, 127.7, 128.3, 129.1, 131.7, 131.8, 139.7,145.1, 149.2, 151.9, 164.3, 168.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₇H₂₉N₄O₅ ⁺ 489.21325; Found 489.2127.

N-(((3aS,6R,6aR)-6-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(141)

Azide 28 was subjected to general procedure 3, followed by generalprocedure 4. White foam, 48.4%. Without NMR- or HRMS analysis, thiscompound was deprotected. The o-cyanobenzamide moiety was converted intothe corresponding phthalimide in the acidic environment of the laststep.

N-(((3aS,6R,6aR)-6-((2-chlorobenzamido)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)pyridazine-4-carboxamide(142)

Azide 29 was subjected to general procedure 3, followed by generalprocedure 4. White foam, 62.7% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 3H) 1.51 (s, 3 H) 3.31 (ddd, J=13.8, 6.8, 4.8 Hz, 1 H) 3.66-3.80 (m, 2 H)3.87 (d, J=10.4 Hz, 1 H) 3.93 (d, J=10.4 Hz, 1 H) 4.01 (dd, J=14.4, 7.3Hz, 1 H) 4.24 (app. t, J=7.8 Hz, 1 H) 4.60 (d, J=0.9 Hz, 1 H) 7.24-7.44(m, 4 H) 7.51-7.59 (m, 1 H) 8.02 (dd, J=5.6, 2.3 Hz, 1 H) 8.66 (t, J=6.2Hz, 1 H) 9.26 (dd, J=5.3, 1.2 Hz, 1 H) 9.63 (dd, J=2.3, 1.2 Hz, 1 H).¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 27.7, 39.6, 43.2, 74.6, 83.7, 85.3,91.8, 113.5, 124.3, 127.1, 129.5, 130.4, 130.8, 131.3, 131.6, 134.7,149.0, 151.8, 164.2, 168.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₄ClN₄O₅ ⁺ 447.14297; Found 447.1428.

N-(((3aS,6R,6aR)-6-([1,1′-biphenyl]-4-carboxamidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)pyridazine-4-carboxamide (143)

Azide 29 was subjected to general procedure 3, followed by generalprocedure 4. White powder, 87.7% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s,3 H) 1.50 (s, 3 H) 3.32 (ddd, J=5.0, 6.5, 13.8 Hz, 1 H) 3.68-3.84 (m, 2H) 3.89 (d, J=10.5 Hz, 1 H) 3.96 (d, J=10.5 Hz, 1 H) 4.10 (dd, J=14.1,7.6 Hz, 1 H) 4.26 (app. dd, J=8.4, 6.9 Hz, 1 H) 4.60 (app. s, 1 H)7.34-7.49 (m, 4 H) 7.54-7.69 (m, 4 H) 7.87-7.96 (m, 2 H) 8.08 (dd,J=5.3, 2.3 Hz, 1 H) 8.74 (dd, J=7.3, 5.3 Hz, 1 H) 9.33 (dd, J=5.3, 1.2Hz, 1 H) 9.76 (dd, J=2.2, 1.3 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm27.68, 27.75, 39.6, 43.2, 74.6, 84.1, 85.5, 91.9, 113.5, 124.5, 127.3,127.4, 127.8, 128.3, 129.0, 131.4, 132.1, 139.8, 145.0, 149.0, 152.0,164.3, 168.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₇H₂₉N₄O₅ ⁺489.21325; Found 489.2126.

N,N′-(((3aS,6R,6aR)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(pyridazine-4-carboxamide)(144)

Azide 29 was subjected to general procedure 3, followed by generalprocedure 4. Yellow foam, 43.6% ¹H NMR (300 MHz, CDCl₃) δ ppm 1.33 (s, 3H) 1.48 (s, 3 H) 3.51 (app. dt, J=14.1, 5.6 Hz, 1 H) 3.70-4.00 (m, 5 H)4.26-4.33 (m, 1 H) 4.53 (d, J=1.5 Hz, 1 H) 8.06 (app. dd, J=5.3, 2.3 Hz,2 H) 8.60-8.73 (m, 2 H) 9.34 (app. td, J=5.4, 1.0 Hz, 2 H) 9.68 (app.dd, J=2.2, 1.3 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.8, 27.9, 40.3,43.5, 74.8, 83.6, 85.1, 92.0, 114.1, 124.7, 124.9, 131.6, 131.9, 148.9,149.1, 152.07, 152.15, 164.4, 164.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcdfor C₁₉H₂₃N₆O₅ ⁺ 415.17244; Found 415.1736.

N-(((3aS,6R,6aR)-6-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)pyridazine-4-carboxamide(145)

Azide 29 was subjected to general procedure 3, followed by generalprocedure 4. White foam, 70.2%. Without NMR- or HRMS analysis, thiscompound was deprotected. The o-cyanobenzamide moiety was converted intothe corresponding phthalimide in the acidic environment of the laststep.

2-chloro-N-(((3aR,4R,6aS)-2,2-dimethyl-6a-((2-phenylacetamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(146)

Azide 30 was subjected to general procedure 3, followed by generalprocedure 4. White foam, 91.9%. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.20 (s, 3H) 1.45 (s, 3 H) 3.23 (ddd, J=14.0, 7.5, 4.8 Hz, 1 H) 3.33 (dd, J=14.2,4.8 Hz, 1 H) 3.56-3.84 (m, 6 H) 4.15-4.22 (m, 1 H) 4.31 (d, J=1.2 Hz, 1H) 6.60 (dd, J=7.2, 4.8 Hz, 1 H) 6.93 (dd, J=7.0, 4.7 Hz, 1 H) 7.20-7.42(m, 8 H) 7.54-7.61 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.5, 27.7,39.7, 42.6, 43.7, 74.7, 83.6, 85.0, 92.0, 113.4, 127.1, 127.4, 129.0,129.4, 129.8, 130.3, 130.8, 131.4, 134.7, 135.0, 167.4, 171.8. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₈ClN₂O₅ ⁺ 459.16813; Found459.1679.

2-chloro-N-(((3aR,4R,6aS)-2,2-dimethyl-6a-((3-phenylpropanamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(147)

Azide 31 was subjected to general procedure 3, followed by generalprocedure 4. White foam, 80.0%. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.31 (s, 3H) 1.48 (s, 3 H) 2.54 (t, J=7.5 Hz, 2 H) 2.84-3.02 (m, 2 H) 3.18 (ddd,J=14.1, 7.0, 4.7 Hz, 1 H) 3.35 (dd, J=14.2, 5.1 Hz, 1 H) 3.57-3.82 (m, 4H) 4.16 (app. t, J=7.3 Hz, 1 H) 4.31 (d, J=1.2 Hz, 1 H) 6.68 (dd, J=6.9,5.4 Hz, 1 H) 6.94 (dd, J=7.3, 4.7 Hz, 1 H) 7.13-7.42 (m, 8 H) 7.55-7.62(m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 31.5, 38.3, 39.5,42.5, 74.6, 83.7, 85.2, 91.9, 113.5, 126.3, 127.1, 128.5, 128.6, 129.8,130.3, 130.8, 131.5, 135.0, 140.9, 167.5, 172.8. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₅H₂₉ClN₂NaO₅ ⁺ 495.16572; Found 495.1664.

N-(((3aR,4R,6aS)-6a-(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)benzamide(148)

Preparation of triflyl azide (TfN₃): NaN₃ (0.68 g, 10.45 mmol) wasdissolved in water (8 mL) and cooled to 0° C. After addition of CH₂Cl₂(8 mL) the mixture was stirred for 15 minutes. Tf₂O (0.352 mL, 2.09mmol) was added dropwise over 1 minute. The RM was stirred vigorously at0° C. and then extracted with DCM (2×3 mL) and washed with aqueoussaturated Na₂CO₃ solution (2×3 mL). The organic layer was saved for thediazo transfer reaction.

Diazo transfer reaction: amine 117 (0.32 g, 1.05 mmol) was dissolved inMeOH (8 mL), giving a clear solution. Et₃N (0.291 mL, 2.09 mmol) wasadded. A freshly prepared solution of CuSO₄ (1.64 mg, 1 mol %) in water(3 mL) was added. The clear solution became turbid. The above-preparedTfN₃ solution was added and the RM was stirred vigorously for 18 h atrt. TLC analysis (toluene/EtOAc 6:4 and CH₂Cl₂/MeOH 9:1) showed completeconsumption of amine and presence of 1 large higher-running spot. The RMwas concentrated in vacuo and adsorbed onto celite. Purification via FCC(toluene/EtOAc 10:0→6:4) gave the title compound as a colourless oil in89.6% yield.

¹H NMR (300 MHz, CDCl₃) δ ppm 1.45 (s, 3 H) 1.53 (s, 3 H) 3.37-3.51 (m,2 H) 3.56 (d, J=12.9 Hz, 1 H) 3.71 (ddd, J=14.0, 6.7, 5.4 Hz, 1 H) 3.85(d, J=10.3 Hz, 1 H) 3.93 (d, J=10.3 Hz, 1 H) 4.23 (ddd, J=7.7, 5.5, 1.8Hz, 1 H) 4.39 (d, J=1.8 Hz, 1 H) 6.67 (t, J=5.3 Hz, 1 H) 7.37-7.53 (m, 3H) 7.74-7.81 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.6, 28.0, 39.9,54.8, 74.9, 84.2, 85.4, 91.8, 114.9, 127.0, 128.7, 131.8, 134.1, 167.9.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₆H₂₁N₄O₄ ⁺ 333.15573; Found333.1568.

N-(((3aR,4R,6aS)-6a-(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N-methylbenzamide(149)

A flask containing a solution of azide 148 (0.30 g, 0.90 mmol) in THF (9mL) was purged with nitrogen gas, treated with NaH (60% dispersion inmineral oil, 72 mg, 1.81 mmol) and backflushed. After 1 hour, MeI (112μL, 1.81 mmol) was added and the whole was stirred at rt overnight. Thereaction was monitored by mass spectrometry (ESI-TOF), which showedcomplete consumption of SM and presence of the desired compound. The RMwas concentrated in vacuo and adsorbed onto celite. Purification viaflash column chromatography (toluene/EtOAc 100:0→70:30) gave the titlecompound in 88.3% yield (transparant oil that solidifies on standing).HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₂₃N₄O₄ ⁺ 347.17138; Found347.1722.

N-(((3aR,4R,6aS)-6a-(benzamidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N-methylbenzamide(150)

Azide 149 was subjected to general procedure 3, followed by procedure 4.White foam, 93.3% HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₃N₂O₅ ⁺425.20710; Found 425.2076.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-methylbenzamide(151)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.34 (s, 3 H) 3.29-3.48 (m, 3 H) 3.49-3.68 (m, 3 H) 3.79 (app. td,J=7.3, 3.8 Hz, 1 H) 3.87 (d, J=9.7 Hz, 1 H) 4.90 (br. s., 2 H) 7.22 (d,J=7.9 Hz, 2 H) 7.38-7.58 (m, 3 H) 7.75 (d, J=7.9 Hz, 2 H) 7.84 (app. d,J=7.0 Hz, 2 H) 8.37 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 20.9,41.9, 44.3, 74.6, 74.7, 78.1, 80.8, 127.27, 127.31, 128.2, 128.7, 131.2,131.7, 134.4, 140.8, 166.2, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₆N₂O₆ ⁺ 385.17580; Found 385.1749.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-fluorobenzamide(152)

General procedure 8. White foam, 91.9% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.37-3.47 (m, 3 H) 3.50-3.64 (m, 3 H) 3.79 (app. td, J=7.3, 3.8 Hz, 1 H)3.87 (d, J=9.7 Hz, 1 H) 4.79 (br. s., 1 H) 4.99 (br. s., 1 H) 7.25 (app.t, J=8.9 Hz, 2 H) 7.41-7.57 (m, 3 H) 7.77-7.87 (m, 2 H) 7.91 (dd, J=8.8,5.6 Hz, 2 H) 8.36 (t, J=5.7 Hz, 1 H) 8.52 (t, J=5.4 Hz, 1 H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ ppm −110.2 (m). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm42.0, 44.2, 74.6, 74.7, 78.1, 80.7, 115.0 (d, J=21.6 Hz), 127.3, 128.2,129.9 (d, J=8.9 Hz), 130.9 (d, J=2.8 Hz), 131.2, 134.4, 163.8 (d,J=248.2 Hz), 165.3, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₂FN₂O₆ 389.15073; Found 389.1496.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-chlorobenzamide(153)

General procedure 8. White foam, 89.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.47 (m, 3 H) 3.50-3.66 (m, 3 H) 3.79 (app. td, J=7.3, 3.7 Hz, 1 H)3.87 (d, J=9.7 Hz, 1 H) 4.79 (s, 1 H) 4.99 (d, J=6.7 Hz, 1 H) 7.36-7.60(m, 5 H) 7.84 (m, 4 H) 8.36 (t, J=5.7 Hz, 1 H) 8.58 (t, J=5.4 Hz, 1 H).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.0, 44.2, 74.6, 74.7, 78.1, 80.7,127.3, 128.22, 128.24, 129.2, 131.2, 133.2, 134.4, 135.8, 165.3, 167.0.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂ClN₂O₆ ⁺ 405.12118; Found405.1209.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-methoxybenzamide(154)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.31-3.47 (m, 3 H) 3.50-3.64 (m, 3 H) 3.72-3.83 (m, 4 H) 3.87 (d, J=9.4Hz, 1 H) 4.88 (br. s., 2 H) 6.90-7.00 (m, 2 H) 7.41-7.57 (m, 3 H)7.75-7.92 (m, 4 H) 8.27-8.41 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm41.9, 44.3, 55.3, 74.6, 74.7, 78.1, 80.9, 113.4, 126.7, 127.3, 128.2,129.1, 131.2, 134.4, 161.4, 165.8, 167.1. HRMS (ESI-TOF) m/z: [M+Na]⁺Calcd for C₂₁H₂₄N₂NaO₆ ⁺ 423.15266; Found 423.1512.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-cyanobenzamide(155)

General procedure 8. White foam, 91.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.49 (m, 3 H) 3.50-3.66 (m, 3 H) 3.79 (app. td, J=7.3, 3.8 Hz, 1 H)3.87 (d, J=9.7 Hz, 1 H) 4.76 (br. s., 1 H) 4.88 (br. s., 1 H) 7.37-7.57(m, 3 H) 7.78-7.86 (m, 2 H) 7.86-7.93 (m, 2 H) 7.94-8.04 (m, 2 H) 8.36(t, J=6.0 Hz, 1 H) 8.77 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 42.0, 44.1, 74.61, 74.64, 78.0, 80.6, 113.4, 118.4, 127.3, 128.1,128.2, 131.2, 132.3, 134.4, 138.5, 165.0, 167.0. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₁H₂₂N₃O₅ ⁺ 396.15540; Found 396.1541.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-(dimethylamino)benzamide(156)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.96 (s, 6 H) 3.27-3.44 (m, 3 H) 3.47-3.62 (m, 3 H) 3.76 (app. td,J=7.3, 3.8 Hz, 1 H) 3.86 (d, J=9.4 Hz, 1 H) 6.63-6.70 (m, 2 H) 7.40-7.57(m, 3 H) 7.68-7.75 (m, 2 H) 7.81-7.87 (m, 2 H) 8.07 (t, J=5.6 Hz, 1 H)8.36 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 39.8, 41.8,44.3, 74.5, 74.7, 78.1, 81.0, 110.8, 121.3, 127.3, 128.2, 128.6, 131.2,134.4, 152.0, 166.2, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₂H₂₈N₃O₅ ⁺ 414.20235; Found 414.2032.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-(trifluoromethyl)benzamide(157)

General procedure 8. White foam, 90.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.51 (m, 3 H) 3.51-3.69 (m, 3 H) 3.81 (app. td, J=7.3, 3.8 Hz, 1 H)3.88 (d, J=9.4 Hz, 1 H) 4.81 (s, 1 H) 5.00 (d, J=6.7 Hz, 1 H) 7.38-7.57(m, 3 H) 7.71-7.90 (m, 4 H) 8.02 (d, J=8.2 Hz, 2 H) 8.37 (t, J=5.9 Hz, 1H) 8.74 (t, J=5.6 Hz, 1 H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −61.7 (s).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.0, 44.1, 74.57, 74.64, 78.1, 80.6,124.0 (q, J=272.3 Hz), 125.2 (q, J=3.7 Hz), 127.3, 128.18, 128.22, 131.0(q, J=31.9 Hz), 131.2, 134.4, 138.3, 165.3, 167.0. HRMS (ESI-TOF) m/z:[M+Na]⁺ Calcd for C₂₁H₂₁F₃N₂NaO₅ ⁺ 461.12948; Found 461.1302.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)isonicotinamide(158)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.49 (m, 3 H) 3.53-3.65 (m, 3 H) 3.80 (app. td, J=7.5, 3.8 Hz, 1 H)3.88 (d, J=9.7 Hz, 1 H) 7.41-7.57 (m, 3 H) 7.80-7.91 (m, 4 H) 8.37 (t,J=5.9 Hz, 1 H) 8.71-8.80 (m, 2 H) 8.88-8.95 (m, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 42.0, 44.2, 74.6, 74.7, 78.0, 80.5, 122.2, 127.3, 128.2,131.2, 134.4, 143.2, 148.5, 164.3, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₉H₂₂N₃O₅ ⁺ 372.15540; Found 372.1552.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(159)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.48 (m, 3 H) 3.52-3.67 (m, 3 H) 3.81 (app. td, J=7.3, 4.1 Hz, 1 H)3.88 (d, J=9.4 Hz, 1 H) 4.80 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H) 7.35-7.57(m, 6 H) 7.68-7.77 (m, 4 H) 7.81-7.87 (m, 2 H) 7.90-7.97 (m, 2 H) 8.38(t, J=6.0 Hz, 1 H) 8.53 (t, J=5.4 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 41.9, 44.2, 74.6, 74.7, 78.1, 80.8, 126.4, 126.8, 127.3, 127.97 (2C), 128.2, 129.0, 131.2, 133.3, 134.4, 139.2, 142.6, 166.0, 167.1. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₆H₂₇N₂O₅ ⁺ 447.19145; Found 447.1930.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-methylbenzamide(160)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, CD₃OD) δ ppm2.36 (s, 3 H) 3.51-3.60 (m, 2 H) 3.60-3.69 (m, 2 H) 3.70-3.78 (m, 2 H)3.90-3.97 (m, 1 H) 3.99 (d, J=10.0 Hz, 1 H) 7.24-7.36 (m, 2 H) 7.37-7.47(m, 2 H) 7.47-7.67 (m, 3 H) 7.73-7.86 (m, 2 H). ¹³C NMR (75 MHz, CD₃OD)δ ppm 21.4, 42.9, 45.7, 76.0, 76.2, 79.8, 82.7, 125.5, 128.3, 128.9,129.4, 129.6, 132.8, 133.3, 135.4, 135.6, 139.5, 170.8, 171.0. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₂O₅ ⁺ 385.17580; Found 385.1776.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-fluorobenzamide(161)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.49 (m, 3 H) 3.50-3.67 (m, 3 H) 3.78 (m, 1 H) 3.88 (d, J=9.7 Hz, 1H) 4.85 (br. s., 2 H) 7.29-7.58 (m, 5 H) 7.60-7.74 (m, 2 H) 7.84 (app.d, J=7.3 Hz, 2H) 8.36 (t, J=5.4 Hz, 1 H) 8.61 (t, J=5.0 Hz, 1 H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ ppm −113.4 (m). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm42.0, 44.2, 74.6, 74.7, 78.1, 80.7, 114.1 (d, J=22.9 Hz), 118.0 (d,J=21.0 Hz), 123.4 (d, J=2.8 Hz), 127.3, 128.2, 130.3 (d, J=8.0 Hz),131.2, 134.4, 136.9 (d, J=6.9 Hz), 161.9 (d, J=243.8 Hz), 165.0 (d,J=2.5 Hz), 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂FN₂O₅ ⁺389.15073; Found 389.1522.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-chlorobenzamide(162)

General procedure 8. White foam, 96.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.69 (m, 6 H) 3.79 (app. td, J=7.3, 4.0 Hz, 1 H) 3.87 (d, J=9.4 Hz,1 H) 4.79 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H) 7.32-7.66 (m, 5 H) 7.70-7.99(m, 4 H) 8.36 (t, J=5.6 Hz, 1 H) 8.65 (t, J=5.0 Hz, 1 H). ¹³C NMR (75MHz, DMSO-d₆) δ ppm 42.1, 44.2, 74.6, 74.7, 78.1, 80.6, 126.0, 127.1,127.3, 128.2, 130.2, 130.9, 131.2, 133.1, 134.4, 136.5, 164.9, 167.1.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂ClN₂O₅ 405.12118; Found405.1194.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-methoxybenzamide(163)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.64 (m, 6 H) 3.70-3.92 (m, 5 H) 4.79 (br. s., 1 H) 5.00 (br. s., 1H) 7.06 (app. d, J=7.9 Hz, 1 H) 7.28-7.60 (m, 6 H) 7.84 (d, J=7.3 Hz, 2H) 8.36 (t, J=5.6 Hz, 1 H) 8.48 (t, J=4.7 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 42.0, 44.3, 55.2, 74.6, 74.8, 78.1, 80.8, 112.3, 117.0,119.5, 127.3, 128.2, 129.3, 131.2, 134.4, 135.9, 159.1, 166.1, 167.1.HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₁H₂₄N₂NaO₆ ⁺ 423.15266; Found423.1511.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-cyanobenzamide(164)

General procedure 8. White foam, 80.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.49 (m, 3 H) 3.52-3.66 (m, 3 H) 3.79 (app. td, J=7.3, 3.5 Hz, 1 H)3.88 (d, J=9.7 Hz, 1 H) 4.69-5.09 (br. s., 2 H) 7.40-7.48 (m, 2 H)7.49-7.56 (m, 1 H) 7.66 (app. t, J=7.9 Hz, 1 H) 7.79-7.87 (m, 2 H) 7.98(app. d, J=7.9 Hz, 1 H) 8.14 (app. d, J=7.9 Hz, 1 H) 8.27 (app. s, 1 H)8.36 (t, J=5.9 Hz, 1 H) 8.74 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 42.1, 44.2, 74.6, 74.7, 78.0, 80.6, 111.4, 118.4, 127.3,128.2, 129.7, 131.0, 131.2, 132.1, 134.4, 134.5, 135.4, 164.6, 167.1.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₂N₃O₅ ⁺ 396.15540; Found396.1544.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-(dimethylamino)benzamide(165)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.93 (s, 6 H) 3.32-3.47 (m, 3 H) 3.47-3.65 (m, 3 H) 3.78 (app. td,J=7.5, 3.8 Hz, 1 H) 3.86 (d, J=9.7 Hz, 1 H) 6.86-6.94 (m, 1 H) 7.12-7.28(m, 3 H) 7.41-7.56 (m, 3 H) 7.79-7.87 (m, 2 H) 8.29-8.43 (m, 2 H). ¹³CNMR (75 MHz, DMSO-d₆) δ ppm 40.7, 42.0, 44.3, 74.6, 74.8, 78.1, 80.9,111.9 (weak), 115.5 (weak), 117.7 (weak), 127.3, 128.2, 128.8, 131.2,134.4, 135.3, 149.5 (weak), 166.8, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₂H₂₈N₃O₅ ⁺ 414.20235; Found 414.2022.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide(166)

General procedure 8. White foam, 98.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.50 (m, 3 H) 3.53-3.66 (m, 3 H) 3.81 (app. td, J=7.5, 3.5 Hz, 1 H)3.88 (d, J=9.7 Hz, 1 H) 4.70-5.09 (br. s., 2 H) 7.40-7.56 (m, 3 H)7.64-7.73 (m, 1 H) 7.80-7.92 (m, 3 H) 8.15 (app. d, J=7.9 Hz, 1 H) 8.21(app. s, 1 H) 8.37 (t, J=5.9 Hz, 1 H) 8.82 (t, J=5.4 Hz, 1 H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ ppm −61.5 (s). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm42.2, 44.2, 74.6, 74.8, 78.1, 80.7, 123.9 (q, J=3.9 Hz), 127.3, 127.7(q, J=272.6 Hz) (weak), 127.7 (q, J=4.2 Hz), 128.2, 129.0 (q, J=32.0Hz), 129.5, 131.2, 131.4, 134.4, 135.3, 164.9, 167.1. HRMS (ESI-TOF)m/z: [M+Na]⁺ Calcd for C₂₁H₂₁F₃N₂NaO₅ ⁺ 461.12948; Found 461.1292.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)nicotinamide(167)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.50 (m, 3 H) 3.53-3.66 (m, 3 H) 3.80 (app. td, J=7.5, 3.5 Hz, 1 H)3.89 (d, J=9.7 Hz, 1 H) 7.42-7.56 (m, 3 H) 7.60 (dd, J=7.9, 5.0 Hz, 1 H)7.79-7.87 (m, 2 H) 8.28-8.41 (m, 2 H) 8.76 (dd, J=5.0, 1.46 Hz, 1 H)8.82 (t, J=5.4 Hz, 1 H) 9.05 (app. d, J=2.1 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 42.0, 44.2, 74.6, 74.7, 78.1, 80.7, 124.1, 127.3, 128.3,130.6, 131.2, 134.4, 136.9, 147.1, 150.1, 164.4, 167.1. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₁₉H₂₂N₃O₆ ⁺ 372.15540; Found 372.1548.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide(168)

General procedure 8. White foam, 78.5% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.50 (m, 3 H) 3.51-3.70 (m, 3 H) 3.76-3.94 (m, 2 H) 4.80 (br. s., 1H) 5.03 (br. s., 1 H) 7.30-7.60 (m, 7 H) 7.66-7.91 (m, 6 H) 8.15 (app.s, 1 H) 8.37 (t, J=5.7 Hz, 1 H) 8.67 (t, J=5.3 Hz, 1 H). ¹³C NMR (75MHz, DMSO-d₆) δ ppm 42.1, 44.3, 74.6, 74.8, 78.1, 80.9, 125.4, 126.6,126.9, 127.3, 127.8, 128.2, 128.9, 129.0, 129.3, 131.2, 134.4, 135.1,139.6, 140.1, 166.3, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₆H₂₇N₂O₆ ⁺ 447.19145; Found 447.1904.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-methylbenzamide(169)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.31 (s, 3 H) 3.36-3.59 (m, 5 H) 3.60-3.67 (m, 1 H) 3.73-3.80 (m, 1 H)3.87 (d, J=9.7 Hz, 1 H) 4.79 (s, 1 H) 4.97 (d, J=6.4 Hz, 1 H) 7.10-7.23(m, 2 H) 7.25-7.33 (m, 2 H) 7.42-7.57 (m, 3 H) 7.80-7.89 (m, 2 H) 8.22(t, J=5.6 Hz, 1 H) 8.36 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 19.4, 41.4, 44.3, 74.6 (2 C), 78.1, 80.8, 125.3, 127.1, 127.3,128.3, 129.1, 130.3, 131.2, 134.4, 135.1, 137.3, 167.1, 169.2. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₂O₅ ⁺ 385.17580; Found 385.1776.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-fluorobenzamide(170)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.68 (m, 6 H) 3.73-3.81 (m, 1 H) 3.88 (d, J=9.4 Hz, 1 H) 4.80 (s, 1H) 4.99 (d, J=6.7 Hz, 1 H) 7.16-7.28 (m, 2 H) 7.40-7.65 (m, 5 H) 7.84(app. d, J=7.0 Hz, 2 H) 8.23 (br. s., 1 H) 8.36 (t, J=5.7 Hz, 1 H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ ppm −114.6 (m). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm41.5, 44.1, 74.35, 74.72, 78.1, 80.4, 116.0 (d, J=22.4 Hz), 124.0 (d,J=14.4 Hz), 124.4 (d, J=3.3 Hz), 127.3, 128.2, 130.1 (d, J=2.8 Hz),131.2, 132.3 (d, J=8.6 Hz), 134.4, 159.1 (d, J=253.2 Hz), 163.8 (d,J=1.4 Hz), 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂FN₂O₅ ⁺389.15073; Found 389.1520.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-chlorobenzamide(171)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.37-3.60 (m, 5 H) 3.63-3.69 (m, 1 H) 3.73-3.80 (m, 1 H) 3.88 (d, J=9.7Hz, 1 H) 4.79 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H) 7.27-7.57 (m, 7 H)7.82-7.89 (m, 2 H) 8.36 (t, J=5.9 Hz, 1 H) 8.46 (t, J=5.7 Hz, 1 H). ¹³CNMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.3, 74.4, 74.8, 78.1, 80.6, 126.9,127.3, 128.3, 128.9, 129.5, 129.9, 130.6, 131.2, 134.4, 137.0, 166.5,167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂ClN₂O₅ ⁺ 405.12118;Found 405.1210.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-methoxybenzamide(172)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.39-3.69 (m, 6 H) 3.72-3.87 (m, 4 H) 3.90 (d, J=9.4 Hz, 1 H) 4.83 (s, 1H) 5.02 (d, J=6.7 Hz, 1 H) 7.00-7.11 (m, 2 H) 7.38-7.54 (m, 4 H)7.77-7.87 (m, 3 H) 8.22 (t, J=5.3 Hz, 1 H) 8.38 (t, J=6.0 Hz, 1 H). ¹³CNMR (75 MHz, DMSO-d₆) δ ppm 41.0, 43.9, 55.9, 74.1, 74.9, 78.2, 80.2,112.1, 120.6, 122.0, 127.3, 128.2, 130.8, 131.2, 132.5, 134.4, 157.1,164.6, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₂O₆ ⁺401.17071; Found 401.1724.

N-(((3S,4R,5R)-5-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(173)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.47 (m, 2 H) 3.51 (d, J=9.7 Hz, 1 H) 3.62-3.95 (m, 5 H) 4.81 (s, 1H) 5.04 (d, J=7.0 Hz, 1 H) 7.41-7.58 (m, 3 H) 7.78-7.93 (m, 6 H) 8.36(t, J=5.9 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 44.1, 48.6, 74.7,75.6, 78.2, 78.6, 123.0, 127.3, 128.2, 131.2, 131.5, 134.40, 134.43,167.1, 167.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₁N₂O₆ ⁺397.13941; Found 397.1400.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-(dimethylamino)benzamide(174)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.63 (s, 6 H) 3.37-3.67 (m, 6 H) 3.75-3.82 (m, 1 H) 3.89 (d, J=9.7 Hz, 1H) 4.82 (s, 1 H) 5.02 (d, J=6.7 Hz, 1 H) 7.08 (app. td, J=7.5, 1.2 Hz, 1H) 7.19 (dd, J=8.1, 1.0 Hz, 1 H) 7.37-7.55 (m, 4 H) 7.74 (dd, J=7.9, 1.8Hz, 1 H) 7.79-7.86 (m, 2 H) 8.39 (t, J=6.0 Hz, 1 H) 9.46 (t, J=5.3 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.0, 44.1, 44.5, 74.2, 74.9, 78.2,80.4, 112.2 (weak), 119.5, 122.6, 127.3, 128.2, 130.2, 131.2, 131.5,134.3, 147.7 (weak), 166.4, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₂H₂₈N₃O₅ ⁺ 414.20235; Found 414.2033.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-(trifluoromethyl)benzamide(175)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.67 (m, 6 H) 3.76 (app. td, J=7.3, 3.7 Hz, 1 H) 3.88 (d, J=9.7 Hz,1 H) 4.79 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H) 7.44-7.64 (m, 6 H) 7.72-7.77(m, 1 H) 7.83-7.88 (m, 2 H) 8.36 (t, J=5.9 Hz, 1 H) 8.54 (t, J=5.7 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.5, 44.3, 74.5, 74.7, 78.0, 80.6,123.8 (q, J=275.9 Hz) (weak), 125.9 (q, J=31.3 Hz), 126.1 (q, J=3.3 Hz),127.3, 128.3, 128.6, 129.5, 131.2, 132.2, 134.4, 136.5 (q, J=2.5 Hz),167.1, 167.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₂F₃N₂O₅ ⁺439.14753; Found 439.1483.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)picolinamide(176)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.66 (m, 6 H) 3.79 (app. td, J=7.3, 4.3 Hz, 1 H) 3.88 (d, J=9.7 Hz,1 H) 4.81 (s, 1 H) 5.03 (d, J=6.7 Hz, 1 H) 7.39-7.62 (m, 4 H) 7.77-7.84(m, 2 H) 7.95-8.07 (m, 2 H) 8.36 (t, J=6.0 Hz, 1 H) 8.53 (t, J=5.9 Hz, 1H) 8.56-8.61 (m, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.2, 44.1, 74.5,74.7, 78.2, 80.5, 121.7, 126.6, 127.3, 128.2, 131.2, 134.4, 137.9,148.4, 149.6, 163.6, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₉H₂₂N₃O₅ ⁺ 372.15540; Found 372.1565.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-[1,1′-biphenyl]-2-carboxamide(177)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.20 (app. dt, J=13.6, 6.6 Hz, 1 H) 3.33-3.44 (m, 3 H) 3.52 (d, J=1.8Hz, 1 H) 3.55 (app. s, 1 H) 3.67 (app. td, J=7.3, 3.8 Hz, 1 H) 3.84 (d,J=9.4 Hz, 1 H) 7.27-7.57 (m, 12 H) 7.81-7.88 (m, 2 H) 8.25 (t, J=5.7 Hz,1 H) 8.34 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.5,44.4, 74.6, 74.7, 78.0, 80.5, 126.9, 127.1, 127.3, 127.8, 128.2, 128.27,128.32, 129.3, 129.8, 131.2, 134.4, 137.2, 139.1, 140.3, 167.1, 169.3.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₆H₂₇N₂O₅ ⁺ 447.19145; Found447.1901.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-bromobenzamide(178)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.33-3.59 (m, 5 H) 3.65-3.69 (m, 1 H)3.74-3.81 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.85 (br. s., 2 H) 7.28-7.39(m, 3 H) 7.43-7.57 (m, 3 H) 7.59-7.65 (m, 1 H) 7.83-7.89 (m, 2 H) 8.36(t, J=6.0 Hz, 1 H) 8.45 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 41.3, 44.3, 74.4, 74.7, 78.1, 80.6, 118.9, 127.33 (2 C), 128.2,128.8, 130.7, 131.2, 132.6, 134.4, 139.2, 167.0, 167.4. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₀H₂₂BrN₂O₅ ⁺ 449.07066; Found 449.0724.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-iodobenzamide(179)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.31-3.60 (m, 5 H) 3.66-3.70 (m, 1 H)3.75-3.82 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.82 (br. s., 2 H) 7.13 (app.td, J=7.5, 1.9 Hz, 1 H) 7.27 (dd, J=7.6, 1.8 Hz, 1 H) 7.36 (app. td,J=7.5, 1.2 Hz, 1 H) 7.42-7.57 (m, 3 H) 7.82-7.90 (m, 3 H) 8.32-8.45 (m,2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.4, 44.3, 74.5, 74.8, 78.1,80.6, 93.5, 127.3, 127.8, 128.1, 128.2, 130.6, 131.2, 134.4, 139.0,143.1, 167.0, 169.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂1N₂O₅497.05679; Found 497.0583.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3,4-dimethylbenzamide(180)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.18-2.32 (2×s, 6 H) 3.32-3.62 (m, 6 H) 3.78 (app. td, J=7.5, 3.8 Hz, 1H) 3.86 (d, J=9.7 Hz, 1 H) 4.77 (br. s., 1 H) 4.99 (br. s., 1 H) 7.17(d, J=7.9 Hz, 1 H) 7.39-7.60 (m, 4 H) 7.64 (app. s, 1 H) 7.78-7.88 (m, 2H) 8.25-8.43 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 19.3, 19.4, 41.9,44.3, 74.6, 74.8, 78.1, 80.9, 124.8, 127.3, 128.25, 128.35, 129.2,131.2, 132.0, 134.4, 136.0, 139.6, 166.4, 167.1. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₂H₂₇N₂O₅ ⁺ 399.19145; Found 399.1901.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3,4-difluorobenzamide(181)

General procedure 8. White foam, 98.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.64 (m, 6 H) 3.78 (app. td, J=7.3, 3.5 Hz, 1 H) 3.87 (d, J=9.7 Hz,1 H) 4.79 (s, 1 H) 4.99 (d, J=6.7 Hz, 1 H) 7.38-7.58 (m, 4 H) 7.70-7.77(m, 1 H) 7.78-7.95 (m, 3 H) 8.36 (t, J=5.9 Hz, 1 H) 8.62 (t, J=5.6 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −138.6 (m), −135.4 (m). ¹³C NMR (75MHz, DMSO-d₆) δ ppm 42.1, 44.2, 74.6, 74.7, 78.1, 80.7, 117.0 (dd,J=56.3, 17.8 Hz), 117.1 (dd, J=55.8, 17.9 Hz), 124.8 (dd, J=7.3, 3.5Hz), 127.3, 128.2, 131.2, 131.9 (dd, J=5.1, 3.5 Hz), 134.4, 149.1 (dd,J=246.0, 12.9 Hz), 152.9 (dd, J=251.0, 12.7 Hz), 164.2 (d, J=1.9 Hz),167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₁F₂N₂O₅ ⁺ 407.14130;Found 407.1397.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3,4-dichlorobenzamide(182)

General procedure 8. White foam, 91.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.65 (m, 6 H) 3.78 (app. td, J=7.4, 3.7 Hz, 1 H) 3.87 (d, J=9.7 Hz,1 H) 4.80 (s, 1 H) 5.00 (d, J=6.7 Hz, 1 H) 7.39-7.56 (m, 3 H) 7.67-7.74(m, 1 H) 7.76-7.89 (m, 3 H) 8.08 (d, J=2.1 Hz, 1 H) 8.36 (t, J=5.7 Hz, 1H) 8.72 (t, J=5.4 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.1, 44.1,74.6, 74.7, 78.1, 80.6, 127.3, 127.6, 128.2, 129.3, 130.6, 131.2, 131.2,133.9, 134.4, 134.8, 164.1, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₁Cl₂N₂O₅ ⁺ 439.08220; Found 439.0821.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3,4-dimethoxybenzamide(183)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.30-3.48 (m, 3 H) 3.50-3.64 (m, 3 H) 3.73-3.83 (m, 7 H) 3.87 (d, J=9.4Hz, 1 H) 6.97 (d, J=8.2 Hz, 1 H) 7.38-7.58 (m, 5 H) 7.79-7.87 (m, 2 H)8.36 (t, J=5.9 Hz, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.0, 44.3,55.5, 55.6, 74.6, 74.7, 78.1, 81.0, 110.7, 110.8, 120.5, 126.7, 127.3,128.2, 131.2, 134.4, 148.1, 151.1, 165.9, 167.1. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₂H₂₇N₂O₇ ⁺ 431.18128; Found 431.1823.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-1-naphthamide(184)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) (majorconformer) δ ppm 3.41-3.54 (m, 3 H) 3.55-3.74 (m, 3 H) 3.85 (app. td,J=7.2, 4.1 Hz, 1 H) 3.91 (d, J=9.4 Hz, 1 H) 4.55 (br. s., 2 H) 7.37-7.65(m, 7 H) 7.82-7.88 (m, 2 H) 7.92-8.01 (m, 2 H) 8.17-8.24 (m, 1 H) 8.38(t, J=5.9 Hz, 1 H) 8.55 (t, J=5.7 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 42.3, 45.0, 75.41 (2 C), 78.8, 81.4, 125.6, 125.8, 126.2, 126.8,127.3, 128.0, 128.8, 128.9, 130.3, 130.5, 131.9, 133.8, 135.1, 135.6,167.8, 169.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₆N₂O₆ ⁺421.17580; Found 421.1768.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-naphthamide(185)

General procedure 8. White foam, 94.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.37-3.52 (m, 3 H) 3.54-3.70 (m, 3 H) 3.79-3.93 (m, 2 H) 4.80 (s, 1 H)5.03 (d, J=6.4 Hz, 1 H) 7.38-7.65 (m, 5 H) 7.79-7.88 (m, 2 H) 7.89-8.04(m, 4 H) 8.37 (t, J=5.9 Hz, 1 H) 8.46 (app. s, 1 H) 8.65 (t, J=5.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.1, 44.3, 74.6, 74.8, 78.1, 80.9,124.3, 126.7, 127.3, 127.51 (2 C), 127.6, 127.8, 128.2, 128.9, 131.22,131.8, 132.1, 134.1, 134.4, 166.5, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₄H₂₆N₂O₆ ⁺ 421.17580; Found 421.1778.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-1-methyl-1H-indole-2-carboxamide(186)

General procedure 8. Pink foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.48 (m, 3 H) 3.50-3.67 (m, 3 H) 3.80 (app. td, J=7.3, 3.8 Hz, 1 H)3.89 (d, J=9.7 Hz, 1 H) 3.96 (s, 3 H) 4.88 (m, 2 H) 7.03-7.13 (m, 2 H)7.26 (app. td, J=7.6, 1.2 Hz, 1 H) 7.38-7.56 (m, 4 H) 7.59 (app. d,J=7.9 Hz, 1 H) 7.79-7.88 (m, 2 H) 8.37 (t, J=5.9 Hz, 1 H) 8.48 (t, J=5.7Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 31.3, 41.4, 44.3, 74.67,74.71, 78.1, 80.8, 104.3, 110.4, 120.0, 121.5, 123.4, 125.6, 127.3,128.2, 131.2, 132.2, 134.4, 138.4, 162.0, 167.1. HRMS (ESI-TOF) m/z:[M+Na]⁺ Calcd for C₂₃H₂₆N₃NaO₆ ⁺ 446.16864; Found 446.1708.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-1-methyl-1H-indole-3-carboxamide(187)

General procedure 8. White foam, 98.9%. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.47 (m, 3 H) 3.54-3.65 (m, 3 H) 3.74-3.84 (m, 4 H) 3.88 (d, J=9.7Hz, 1 H) 4.93 (br. s., 2 H) 7.10-7.24 (m, 2 H) 7.38-7.55 (m, 4 H)7.78-7.87 (m, 3 H) 8.02 (s, 1 H) 8.14 (dd, J=7.6, 1.2 Hz, 1 H) 8.36 (t,J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 33.0, 41.1, 44.3, 74.60(2 C), 78.1, 81.3, 109.5, 110.2, 120.6, 121.1, 121.9, 126.5, 127.3,128.2, 131.2, 131.9, 134.4, 136.7, 164.4, 167.1. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₃H₂₆N₃O₅ ⁺ 424.18670; Found 424.1888.

N,N′-(((2R,3R,4S)-3,4-dihydroxytetrahydrofuran-2,4-diyl)bis(methylene))dibenzamide(188)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.63 (m, 6 H) 3.79 (app. td, J=7.4, 4.0 Hz, 1 H) 3.87 (d, J=9.7 Hz,1 H) 4.78 (br. s., 1 H) 4.99 (d, J=6.4 Hz, 1 H) 7.26-7.65 (m, 6 H) 7.84(app. d, J=7.9 Hz, 4 H) 8.36 (t, J=5.9 Hz, 1 H) 8.47 (t, J=5.3 Hz, 1 H).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.0, 44.3, 74.6, 74.8, 78.1, 80.8,127.27, 127.33, 128.2, 128.3, 131.1, 131.2, 134.4, 134.5, 166.4, 167.1.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₃N₂O₅ ⁺ 371.16015; Found371.1595.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((2-phenylacetamido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(189)

General procedure 8. White foam, 94.9% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.10-3.19 (m, 1 H) 3.32-3.47 (m, 5 H) 3.49-59 (m, 2 H) 3.64 (app. td,J=7.3, 3.1 Hz, 1 H) 3.86 (d, J=9.7 Hz, 1 H) 4.78 (br. s., 1 H) 4.95 (br.s., 1 H) 7.12-7.36 (m, 5 H) 7.39-7.59 (m, 3 H) 7.79-7.94 (m, 2 H) 8.10(t, J=5.3 Hz, 1 H) 8.34 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 41.0, 42.2, 44.3, 74.2, 74.8, 78.0, 81.0, 126.2, 127.3, 128.1,128.2, 129.0, 131.2, 134.4, 136.6, 167.0, 170.2. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₁H₂₅N₂O₅ ⁺ 385.17580; Found 385.1769.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((3-phenylpropanamido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(190)

General procedure 8. White foam, 98.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.38 (t, J=7.9 Hz, 2 H) 2.78 (t, J=7.8 Hz, 2 H) 3.06-3.20 (m, 1 H)3.29-3.68 (m, 6 H) 3.85 (d, J=9.4 Hz, 1 H) 4.79 (br. s., 2 H) 7.03-7.35(m, 5 H) 7.36-7.61 (m, 3 H) 7.73-8.01 (m, 3 H) 8.34 (t, J=5.4 Hz, 1 H).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 31.1, 36.8, 40.9, 44.3, 74.2, 74.7,77.9, 81.0, 125.8, 127.3, 128.16, 128.23 (2 C), 131.2, 134.4, 141.4,167.0, 171.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₇N₂O₅ ⁺399.19145; Found 399.1931.

N-(((3S,4R,5R)-5-(cyclohexanecarboxamidomethyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(191)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.07-1.37 (m, 5 H) 1.49-1.75 (m, 5 H) 2.11 (tt, J=11.1, 2.9 Hz, 1 H)3.12-3.22 (m, 1 H) 3.25-3.46 (m, 3 H) 3.48-3.57 (m, 2 H) 3.58-3.65 (m, 1H) 3.84 (d, J=9.7 Hz, 1 H) 4.80 (br. s., 2 H) 7.41-7.58 (m, 3 H) 7.67(t, J=5.6 Hz, 1 H) 7.80-7.90 (m, 2 H) 8.34 (t, J=5.9 Hz, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 25.27, 25.31, 25.5, 29.2, 29.4, 40.5, 43.8,44.1, 74.0, 74.6, 78.0, 80.9, 127.3, 128.3, 131.2, 134.4, 167.0, 175.4.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₉N₂O₅ ⁺ 377.20710; Found377.2086.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2,6-dichlorobenzamide (192)

General procedure 8. White foam ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.49 (m, 3 H) 3.53-3.62 (m, 2 H) 3.65-3.72 (m, 1 H) 3.74-3.80 (m, 1H) 3.88 (d, J=9.7 Hz, 1 H) 4.76 (s, 1 H) 5.04 (d, J=6.7 Hz, 1 H)7.36-7.57 (m, 6 H) 7.81-7.89 (m, 2 H) 8.32 (t, J=5.9 Hz, 1 H) 8.74 (t,J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.1, 44.4, 74.2, 74.9,78.0, 80.7, 127.3, 127.9, 128.2, 130.7, 131.1, 131.2, 134.4, 136.8,163.8, 167.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₁Cl₂N₂O₅ ⁺439.08220; Found 439.0826.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2,4-dichlorobenzamide (193)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.59 (m, 5 H) 3.65 (d, J=7.9 Hz, 1 H) 3.76 (app. td, J=7.1, 3.7 Hz,1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.86 (br. s., 2 H) 7.39 (app. d, J=1.2 Hz,2 H) 7.43-7.57 (m, 3 H) 7.64 (app. t, J=1.2 Hz, 1 H) 7.82-7.88 (m, 2 H)8.36 (t, J=5.9 Hz, 1 H) 8.54 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 41.3, 44.2, 74.4, 74.8, 78.1, 80.6, 127.1, 127.4, 128.3,129.0, 130.3, 131.16, 131.24, 134.3, 134.4, 135.9, 165.6, 167.1. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₁Cl₂N₂O₅ ⁺ 439.08220; Found439.0835.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2,4,6-trichlorobenzamide(194)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.32-3.45 (m, 3 H) 3.53-3.63 (m, 2 H) 3.67 (d, J=8.2 Hz, 1 H) 3.72-3.79(m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.78 (br. s., 1 H) 5.05 (br. s., 1 H)7.42-7.57 (m, 3 H) 7.69 (s, 2 H) 7.80-7.89 (m, 2 H) 8.32 (t, J=6.0 Hz, 1H) 8.77 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.0, 44.4,74.1, 74.9, 78.0, 80.6, 127.4, 127.7, 128.2, 131.2, 132.1, 134.0, 134.4,135.8, 163.1, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₀Cl₃N₂O₅⁺ 473.04323; Found 473.0438.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3,5-dichloroisonicotinamide (195)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.46 (m, 3 H) 3.56-3.72 (m, 3 H) 3.73-3.81 (m, 1 H) 3.90 (d, J=9.4Hz, 1 H) 4.80 (s, 1 H) 5.07 (d, J=6.7 Hz, 1 H) 7.43-7.57 (m, 3 H)7.81-7.89 (m, 2 H) 8.33 (t, J=5.9 Hz, 1 H) 8.66 (s, 2 H) 8.96 (t, J=5.6Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 40.9, 44.3, 74.0, 74.9, 78.0,80.5, 127.3, 128.17, 128.22, 131.2, 134.4, 143.2, 147.4, 161.8, 167.0.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₀Cl₂N₃O₅ ⁺ 440.07745; Found440.0761.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2,4-dichloronicotinamide (196)

General procedure 8. White foam, 58.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.49 (m, 3 H) 3.55-3.71 (m, 3 H) 3.73-3.80 (m, 1 H) 3.89 (d, J=9.4Hz, 1 H) 4.79 (br. s., 1 H) 5.06 (br. s., 1 H) 7.41-7.57 (m, 3 H) 7.64(d, J=5.3 Hz, 1 H) 7.81-7.89 (m, 2 H) 8.33 (t, J=6.0 Hz, 1 H) 8.39 (d,J=5.3 Hz, 1 H) 8.88 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm41.0, 44.3, 74.1, 74.9, 78.0, 80.5, 124.0, 127.3, 128.2, 131.2, 132.8,134.4, 142.0, 147.6, 149.9, 162.5, 167.0. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₉H₂₀Cl₂N₃O₅ ⁺ 440.07745; Found 440.0767.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2,6-dichloronicotinamide (197)

General procedure 8. White foam, 62.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.68 (m, 6 H) 3.72-3.79 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1H) 5.03 (d, J=7.0 Hz, 1 H) 7.42-7.59 (m, 4 H) 7.82-7.88 (m, 2 H) 7.90(d, J=7.9 Hz, 1 H) 8.37 (t, J=5.9 Hz, 1 H) 8.71 (t, J=5.6 Hz, 1 H). ¹³CNMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.2, 74.2, 74.8, 78.0, 80.4, 123.4,127.3, 128.2, 131.2, 132.4, 134.4, 141.1, 145.8, 148.9, 164.3, 167.0.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₀Cl₂N₃O₅ ⁺ 440.07745; Found440.0777.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4,6-dichloronicotinamide (198)

General procedure 8. White foam, 86.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.32-3.71 (m, 6 H) 3.71-3.81 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1H) 5.04 (d, J=6.7 Hz, 1 H) 7.41-7.59 (m, 3 H) 7.78-7.95 (m, 3 H) 8.36(t, J=5.9 Hz, 1 H) 8.44 (s, 1 H) 8.77 (t, J=5.6 Hz, 1 H). ¹³C NMR (75MHz, DMSO-d₆) δ ppm 41.3, 44.2, 74.3, 74.8, 78.0, 80.4, 124.6, 127.3,128.2, 131.2, 132.0, 134.4, 142.5, 149.0, 151.0, 163.4, 167.0. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₀Cl₂N₃O₅ ⁺ 440.07745; Found440.0770.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-chloronicotinamide(199)

General procedure 8. White foam ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.70 (m, 6 H) 3.74-3.81 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1H) 5.03 (d, J=6.7 Hz, 1 H) 7.38-7.57 (m, 4 H) 7.78-7.90 (m, 3 H) 8.37(t, J=5.9 Hz, 1 H) 8.44 (dd, J=4.8, 1.9 Hz, 1 H) 8.67 (t, J=5.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.2, 74.3, 74.8, 78.0, 80.5,122.9, 127.3, 128.2, 131.2, 133.3, 134.4, 138.0, 146.5, 150.0, 165.3,167.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₁ClN₃O₅ ⁺ 406.11642;Found 406.1180.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-3-chloroisonicotinamide(200)

General procedure 8. White foam ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.69 (m, 6 H) 3.73-3.80 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1H) 5.03 (d, J=6.7 Hz, 1 H) 7.39 (d, J=5.0 Hz, 1 H) 7.43-7.58 (m, 3 H)7.81-7.91 (m, 2 H) 8.37 (t, J=5.9 Hz, 1 H) 8.50 (app. d, J=5.0 Hz, 1 H)8.67 (app. s, 1 H) 8.74 (t, J=5.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 41.1, 44.2, 74.2, 74.8, 78.1, 80.4, 122.8, 127.3, 127.4, 128.2,131.2, 134.4, 143.6, 148.1, 149.2, 164.6, 167.0. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₁₉H₂₁ClN₃O₅ ⁺ 406.11642; Found 406.1170.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-4-chloronicotinamide(201)

General procedure 8. White foam ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.61 (m, 5 H) 3.63-3.71 (m, 1 H) 3.74-3.82 (m, 1 H) 3.89 (d, J=9.7Hz, 1 H) 4.81 (br. s., 1 H) 5.05 (br. s., 1 H) 7.40-7.57 (m, 3 H) 7.58(d, J=5.3 Hz, 1 H) 7.82-7.89 (m, 2 H) 8.36 (t, J=5.9 Hz, 1 H) 8.53-8.59(m, 2 H) 8.74 (t, J=5.7 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.4,44.3, 74.4, 74.8, 78.1, 80.5, 124.7, 127.3, 128.2, 131.2, 132.7, 134.4,140.0, 149.1, 151.1, 164.3, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₉H₂₁ClN₃O₅ ⁺ 406.11642; Found 406.1169.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-6-chloronicotinamide(202)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.49 (m, 3 H) 3.52-3.66 (m, 3 H) 3.79 (app. td, J=7.4, 3.7 Hz, 1 H)3.88 (d, J=9.7 Hz, 1 H) 4.80 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H) 7.40-7.49(m, 2 H) 7.49-7.56 (m, 1 H) 7.59 (dd, J=8.4, 0.7 Hz, 1 H) 7.78-7.87 (m,2 H) 8.21 (dd, J=8.4, 2.5 Hz, 1 H) 8.36 (t, J=5.9 Hz, 1 H) 8.75-8.87 (m,2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.9, 44.1, 74.5, 74.7, 78.0,80.6, 124.0, 127.3, 128.2, 129.3, 131.2, 134.3, 138.6, 149.0, 152.4,163.9, 167.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₁ClN₃O₅ ⁺406.11642; Found 406.1166.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyrimidine-2-carboxamide(203)

General procedure 8. White foam, 54.5% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.67 (m, 6 H) 3.76-3.84 (m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1H) 5.04 (d, J=6.7 Hz, 1 H) 7.40-7.56 (m, 3 H) 7.66 (t, J=5.0 Hz, 1 H)7.77-7.86 (m, 2 H) 8.36 (t, J=5.9 Hz, 1 H) 8.64 (t, J=5.7 Hz, 1 H) 8.92(d, J=5.0 Hz, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.5, 44.1, 74.5,74.8, 78.1, 80.4, 123.0, 127.3, 128.2, 131.2, 134.4, 157.7, 157.8,162.2, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₁N₄O₅ ⁺373.15065; Found 373.1517.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyrimidine-4-carboxamide(204)

General procedure 8. White foam, 65.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.46 (m, 2 H) 3.47-3.67 (m, 4 H) 3.77-3.85 (m, 1 H) 3.88 (d, J=9.7Hz, 1 H) 4.81 (s, 1 H) 5.02 (d, J=7.0 Hz, 1 H) 7.39-7.47 (m, 2 H)7.49-7.55 (m, 1 H) 7.76-7.84 (m, 2 H) 8.01 (dd, J=5.0, 1.5 Hz, 1 H) 8.36(t, J=6.0 Hz, 1 H) 8.74 (t, J=6.0 Hz, 1 H) 9.06 (d, J=5.0 Hz, 1 H) 9.26(d, J=1.5 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.4, 44.0, 74.5,74.7, 78.1, 80.3, 118.4, 127.3, 128.2, 131.2, 134.4, 156.2, 157.8,159.7, 162.5, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₁N₄O₅ ⁺373.15065; Found 373.1522.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyrimidine-5-carboxamide(205)

General procedure 8. White foam, 61.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.51 (m, 3 H) 3.54-3.68 (m, 3 H) 3.80 (app. td, J=7.4, 3.7 Hz, 1 H)3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1 H) 5.03 (d, J=6.7 Hz, 1 H) 7.39-7.49(m, 2 H) 7.49-7.56 (m, 1 H) 7.78-7.86 (m, 2 H) 8.37 (t, J=5.9 Hz, 1 H)8.93 (t, J=5.6 Hz, 1 H) 9.14 (app. s, 2 H) 9.29 (app. s, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 41.8, 44.2, 74.5, 74.7, 78.1, 80.6, 127.3,127.9, 128.3, 131.3, 134.4, 155.9, 159.9, 163.3, 167.1. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₁₈H₂₁N₄O₅ ⁺ 373.15065; Found 373.1517.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyridazine-3-carboxamide(206)

General procedure 8. White foam, 58.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36-3.48 (m, 2 H) 3.49-3.72 (m, 4 H) 3.79-3.92 (m, 2 H) 4.81 (s, 1 H)5.03 (d, J=6.7 Hz, 1 H) 7.38-7.48 (m, 2 H) 7.48-7.55 (m, 1 H) 7.78-7.85(m, 2 H) 7.90 (dd, J=8.4, 5.1 Hz, 1 H) 8.20 (dd, J=8.5, 1.8 Hz, 1 H)8.36 (t, J=6.0 Hz, 1 H) 8.99 (t, J=6.0 Hz, 1 H) 9.40 (dd, J=5.0, 1.8 Hz,1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.9, 44.5, 75.0, 75.2, 78.8,80.8, 126.3, 127.7, 129.0, 129.3, 132.1, 134.6, 153.1, 153.9, 163.5,168.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₁N₄O₅ ⁺ 373.15065;Found 373.1520.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyridazine-4-carboxamide(207)

General procedure 8. White foam, 52.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.51 (m, 3 H) 3.52-3.67 (m, 3 H) 3.79 (app. td, J=7.5, 3.7 Hz, 1 H)3.89 (d, J=9.7 Hz, 1 H) 4.81 (s, 1 H) 5.03 (d, J=6.7 Hz, 1 H) 7.39-7.48(m, 2 H) 7.49-7.56 (m, 1 H) 7.78-7.87 (m, 2 H) 7.96 (dd, J=5.3, 2.3 Hz,1 H) 8.36 (t, J=6.0 Hz, 1 H) 9.07 (t, J=5.4 Hz, 1 H) 9.38 (dd, J=5.3,1.2 Hz, 1 H) 9.52 (dd, J=2.2, 1.3 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 42.0, 44.1, 74.5, 74.7, 78.0, 80.5, 124.2, 127.3, 128.2, 131.2,131.5, 134.4, 148.9, 152.0, 163.4, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₈H₂₁N₄O₅ ⁺ 373.15065; Found 373.1523.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyrazine-2-carboxamide(208)

General procedure 8. White foam, 63.5% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.47 (m, 2 H) 3.48-3.67 (m, 4 H) 3.77-3.84 (m, 1 H) 3.88 (d, J=9.7Hz, 1 H) 4.81 (s, 1 H) 5.02 (d, J=6.7 Hz, 1 H) 7.39-7.47 (m, 2 H)7.49-7.55 (m, 1 H) 7.76-7.85 (m, 2 H) 8.35 (t, J=5.9 Hz, 1 H) 8.61 (t,J=5.9 Hz, 1 H) 8.66 (dd, J=2.6, 1.5 Hz, 1 H) 8.85 (d, J=2.3 Hz, 1 H)9.17 (d, J=1.5 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.2, 44.0,74.5, 74.7, 78.1, 80.4, 127.3, 128.2, 131.2, 134.4, 143.3, 143.4, 144.5,147.6, 162.7, 167.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₁N₄O₅ ⁺373.15065; Found 373.1514.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide(209)

General procedure 8. White foam, 84.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.63 (m, 6 H) 3.76 (app. dt, J=7.5, 3.9 Hz, 1 H) 3.87 (d, J=9.4 Hz,1 H) 4.03 (s, 3 H) 4.80 (s, 1 H) 5.01 (d, J=7.0 Hz, 1 H) 6.86 (d, J=2.1Hz, 1 H) 7.41 (d, J=2.1 Hz, 1 H) 7.42-7.57 (m, 3 H) 7.80-7.88 (m, 2 H)8.37 (t, J=6.0 Hz, 1 H) 8.49 (t, J=5.7 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 38.9, 41.4, 44.2, 74.64 (2 C), 78.0, 80.7, 107.3, 127.3,128.2, 131.2, 134.4, 135.2, 137.1, 159.5, 167.1. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₁₈H₂₃N₄O₅ ⁺ 375.16630; Found 375.1674.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-1-methyl-1H-imidazole-5-carboxamide(210)

General procedure 8. White foam, 96.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.25-3.63 (m, 6 H) 3.69-3.83 (m, 4 H) 3.87 (d, J=9.7 Hz, 1 H) 4.80 (s, 1H) 5.00 (d, J=6.7 Hz, 1 H) 7.41-7.57 (m, 3 H) 7.60 (app. s, 1 H) 7.71(app. s, 1 H) 7.80-7.87 (m, 2 H) 8.29 (t, J=5.6 Hz, 1 H) 8.37 (t, J=5.9Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 33.5, 41.1, 44.3, 74.65 (2 C),78.0, 81.0, 125.8, 127.3, 128.2, 131.2, 132.0, 134.4, 141.7, 160.0,167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₃N₄O₅ ⁺ 375.16630;Found 375.1674.

N-(((3S,4R,5R)-3,4-dihydroxy-5-(methylsulfonamidomethyl)tetrahydrofuran-3-yl)methyl)benzamide(211)

General procedure 8. White foam, 81.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.89 (s, 3 H) 3.03 (app. dt, J=13.4, 6.6 Hz, 1 H) 3.24 (ddd, J=13.7,5.8, 3.1 Hz, 1 H) 3.42 (m, 2 H) 3.55-3.71 (m, 3 H) 3.87 (d, J=9.7 Hz, 1H) 4.81 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H) 7.05 (t, J=6.2 Hz, 1 H)7.43-7.57 (m, 3 H) 7.82-7.88 (m, 2 H) 8.35 (t, J=5.9 Hz, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 39.6, 44.2, 44.9, 73.9, 74.8, 77.9, 81.1, 127.3,128.2, 131.2, 134.4, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₄H₂₁N₂O₆S⁺ 345.11148; Found 345.1107.

N-(((3S,4R,5R)-5-(ethylsulfonamidomethyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(212)

General procedure 8. White foam, 78.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.17 (t, J=7.3 Hz, 3 H) 2.92-3.08 (m, 3 H) 3.23 (ddd, J=13.8, 5.8, 2.9Hz, 1 H) 3.35-3.48 (m, 2 H) 3.53-3.70 (m, 3 H) 3.87 (d, J=9.7 Hz, 1 H)4.80 (s, 1 H) 4.99 (d, J=6.4 Hz, 1 H) 7.10 (t, J=5.9 Hz, 1 H) 7.42-7.58(m, 3 H) 7.80-7.89 (m, 2 H) 8.35 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 8.1, 44.2, 44.7, 45.7, 74.0, 74.8, 78.0, 81.2, 127.3,128.2, 131.2, 134.4, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₅H₂₃N₂O₆S⁺ 359.12713; Found 359.1285.

N-(((3S,4R,5R)-3,4-dihydroxy-5-(((1-methylethyl)sulfonamido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(213)

General procedure 8. White foam, 86.8% ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.19 (d, J=2.1 Hz, 3 H) 1.21 (d, J=2.1, 3 H) 3.03 (app. dt, J=13.6, 6.6Hz, 1 H) 3.12-3.30 (m, 2 H) 3.35-3.48 (m, 2 H) 3.54-3.69 (m, 3 H) 3.87(d, J=9.4 Hz, 1 H) 4.80 (s, 1 H) 4.98 (d, J=6.7 Hz, 1 H) 7.08 (t, J=5.9Hz, 1 H) 7.43-7.57 (m, 3 H) 7.82-7.88 (m, 2 H) 8.34 (t, J=6.0 Hz, 1 H).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 16.3 (2 C), 44.2, 45.0, 51.6, 74.0,74.8, 78.0, 81.4, 127.3, 128.2, 131.2, 134.4, 167.1. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₁₆H₂₅N₂O₆S⁺ 373.14278; Found 373.1445.

N-(((3S,4R,5R)-3,4-dihydroxy-5-(((trifluoromethyl)sulfonamido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(214)

General procedure 8. White foam, 83.6% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.17-3.25 (m, 1 H) 3.36-3.48 (m, 3 H) 3.56-3.64 (m, 2 H) 3.67-3.74 (m, 1H) 3.89 (d, J=9.7 Hz, 1 H) 4.85 (s, 1 H) 5.09 (d, J=6.6 Hz, 1 H)7.43-7.57 (m, 3 H) 7.81-7.88 (m, 2 H) 8.36 (t, J=6.0 Hz, 1 H) 9.56 (br.s, 1 H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −77.6 (s). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 44.1, 45.9, 73.9, 74.9, 78.0, 80.5, 119.7 (q, J=322.7Hz), 127.3, 128.2, 131.2, 134.4, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcdfor C₁₄H₁₈F₃N₂O₆S⁺ 399.08322; Found 399.0831.

N-(((3S,4R,5R)-3,4-dihydroxy-5-(phenylsulfonamidomethyl)tetrahydrofuran-3-yl)methyl)benzamide(215)

General procedure 8. White foam, 92.9% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.82 (app. dt, J=13.3, 6.7 Hz, 1 H) 3.00 (ddd, J=13.0, 5.7, 2.6 Hz, 1H)3.33-3.44 (m, 2 H) 3.48-3.65 (m, 3 H) 3.80 (d, J=9.7 Hz, 1 H) 4.76 (s, 1H) 4.99 (d, J=6.7 Hz, 1 H) 7.36-7.68 (m, 6 H) 7.72 (t, J=6.0 Hz, 1 H)7.75-7.90 (m, 4 H) 8.31 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 44.3, 45.1, 74.1, 74.8, 77.9, 80.7, 126.5, 127.3, 128.3, 129.1,131.2, 132.3, 134.4, 140.5, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₉H₂₃N₂O₆S⁺ 407.12713; Found 407.1266.

N-(((3S,4R,5R)-3,4-dihydroxy-5-(((4-methylphenyl)sulfonamido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(216)

General procedure 8. White foam, 77.5% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.38 (s, 3 H) 2.80 (app. dt, J=13.0, 6.4 Hz, 1 H) 2.93-3.02 (m, 1 H)3.35-3.47 (m, 2 H) 3.50-3.66 (m, 3 H) 3.82 (d, J=9.7 Hz, 1 H) 4.77 (s, 1H) 5.00 (d, J=6.4 Hz, 1 H) 7.38 (d, J=8.2 Hz, 2 H) 7.43-7.57 (m, 3 H)7.63 (t, J=5.6 Hz, 1 H) 7.69 (d, J=8.2 Hz, 2 H) 7.80-7.88 (m, 2 H) 8.32(t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 21.0, 44.3, 45.1,74.1, 74.8, 77.9, 80.7, 126.6, 127.3, 128.2, 129.5, 131.2, 134.4, 137.6,142.5, 167.1. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd for C₂₀H₂₃N₂O₆S⁻419.12823; Found 419.1286.

N-(((3S,4R,5R)-5-(((4-chlorophenyl)sulfonamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(217)

General procedure 8. White foam, 67.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.83 (app. dd, J=13.0, 6.6 Hz, 1 H) 3.00-3.04 (m, 1 H) 3.33-3.46 (m, 2H) 3.47-3.66 (m, 3 H) 3.79 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H) 4.99 (d,J=5.3 Hz, 1H) 7.40-7.49 (m, 2 H) 7.50-7.56 (m, 1 H) 7.61-7.71 (m, 2 H)7.74-7.91 (m, 5 H) 8.31 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 44.3, 45.1, 74.0, 74.8, 77.9, 80.6, 127.3, 128.2, 128.5, 129.2,131.2, 134.4, 137.1, 139.5, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₉H₂₂ClN₂O₆S⁺ 441.08816; Found 441.0902.

N-(((3S,4R,5R)-5-(((2-chlorophenyl)sulfonamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(218)

General procedure 8. White foam, 64.8% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.97 (app. dt, J=13.6, 6.6 Hz, 1 H) 3.17 (ddd, J=13.8, 5.6, 2.9 Hz, 1H)3.31-3.49 (m, 3 H) 3.54 (d, J=7.9 Hz, 1 H) 3.62 (app. td, J=7.5, 2.9 Hz,1 H) 3.72 (d, J=9.7 Hz, 1 H) 4.81 (br. s., 2 H) 7.40-7.67 (m, 6 H)7.80-7.88 (m, 2 H) 7.89-7.99 (m, 2 H) 8.29 (t, J=6.0 Hz, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 44.3, 45.0, 74.1, 74.8, 77.9, 80.6, 127.3,127.5, 128.2, 130.2, 130.6, 131.2, 131.6, 133.7, 134.4, 138.3, 167.0.HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd for C₁₉H₂₀ClN₂O₆S⁻ 439.07361; Found439.0734.

N-(((3S,4R,5R)-5-(([1,1′-biphenyl]-4-sulfonamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(219)

General procedure 8. White foam, 63.0% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.86 (app. dt, J=13.2, 6.6 Hz, 1 H) 3.05 (ddd, J=13.2, 5.6, 2.9 Hz, 1 H)3.39 (m, 2 H) 3.50-3.69 (m, 3 H) 3.82 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H)5.01 (d, J=6.7 Hz, 1 H) 7.38-7.57 (m, 6 H) 7.69-7.90 (m, 9 H) 8.32 (t,J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 45.0, 45.8, 74.7, 75.5,78.6, 81.4, 127.8, 127.9, 128.01 (2 C), 128.9, 129.1, 129.8, 131.9,135.1, 139.3, 140.0, 144.5, 167.8. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd forC₂₅H₂₅N₂O₆S⁻ 481.14388; Found 481.1446.

N-(((3S,4R,5R)-5-(([1,1′-biphenyl]-2-sulfonamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(220)

General procedure 8. White foam, 92.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.78 (app. dt, J=13.5, 6.7 Hz, 1 H) 2.98 (ddd, J=13.4, 5.6, 3.0 Hz, 1H)3.32-3.43 (m, 2 H) 3.48-3.61 (m, 3 H) 3.80 (d, J=9.4 Hz, 1 H) 4.82 (br.s., 2 H) 7.16 (t, J=5.9 Hz, 1 H) 7.29-7.69 (m, 11 H) 7.80-7.87 (m, 2 H)7.96 (dd, J=7.8, 1.3 Hz, 1 H) 8.31 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 44.2, 45.0, 74.0, 74.8, 77.9, 80.7, 127.3, 127.4, 127.6,127.7, 127.8, 128.2, 129.2, 131.2, 131.8, 132.7, 134.4, 139.2, 139.7,140.6, 167.1. HRMS (ESI-TOF) m/z: [M−H]⁻ Calcd for C₂₅H₂₅N₂O₆S⁻481.14388; Found 481.1450.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)tetrahydrofuran-3-yl)methyl)benzamide(221)

General procedure 8. White foam, 83.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.36 (dd, J=13.6, 6.0 Hz, 1 H) 3.44 (dd, J=13.5, 6.2 Hz, 1 H) 3.59 (d,J=9.7 Hz, 1 H) 3.65 (d, J=8.2 Hz, 1 H) 3.84 (d, J=9.7 Hz, 1 H) 4.02(app. td, J=7.7, 3.2 Hz, 1 H) 4.52 (dd, J=14.2, 7.5 Hz, 1 H) 4.67 (dd,J=14.2, 3.1 Hz, 1 H) 7.29-7.54 (m, 6 H) 7.77-7.86 (m, 4 H) 8.37 (t,J=6.0 Hz, 1 H) 8.48 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 43.6,51.9, 73.8, 74.9, 78.0, 80.2, 122.1, 125.2, 127.3, 127.8, 128.2, 128.9,130.8, 131.2, 134.4, 146.3, 167.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₃N₄O₄ ⁺ 395.17138; Found 395.1730.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((5-phenyl-1H-1,2,3-triazol-1-yl)methyl)tetrahydrofuran-3-yl)methyl)benzamide(222)

General procedure 8. Light brown colored foam, 90.9% ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.32-3.46 (m, 2 H) 3.50 (d, J=9.7 Hz, 1 H) 3.69-3.82 (m,2 H) 4.05 (app. td, J=8.2, 2.9 Hz, 1 H) 4.42 (dd, J=14.4, 8.2 Hz, 1 H)4.64 (dd, J=14.4, 2.9 Hz, 1 H) 4.88 (br. s., 1 H) 5.18 (br. s., 1 H)7.41-7.64 (m, 8 H) 7.78-7.87 (m, 3 H) 8.34 (t, J=5.9 Hz, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 44.4, 50.8, 75.0, 75.2, 78.6, 81.0, 127.1,127.8, 129.1, 129.4, 129.7, 130.0, 132.2, 133.2, 134.6, 139.1, 168.4.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₃N₄O₄ ⁺ 395.17138; Found395.1724.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((3-phenylureido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(223)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.19 (m, 1 H) 3.35-3.50 (m, 3 H) 3.53-3.63 (m, 2 H) 3.63-3.70 (m, 1 H)3.89 (d, J=9.4 Hz, 1 H) 4.79 (s, 1 H) 5.00 (d, J=6.7 Hz, 1 H) 6.17 (t,J=5.4 Hz, 1 H) 6.88 (app. t, J=7.3 Hz, 1 H) 7.21 (app. t, J=7.9 Hz, 2 H)7.30-7.58 (m, 5 H) 7.77-7.91 (m, 2 H) 8.37 (t, J=5.9 Hz, 1 H) 8.50 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.2, 44.2, 73.9, 74.8, 78.2, 81.2,117.5, 121.0, 127.3, 128.3, 128.7, 131.2, 134.5, 140.5, 155.2, 167.2.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₄N₃O₅ ⁺ 386.17105; Found386.1708.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((3-phenylthioureido)methyl)tetrahydrofuran-3-yl)methyl)benzamide(224)

General procedure 8. White foam, 85.8% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.40-3.65 (m, 5 H) 3.76-3.93 (m, 3 H) 4.86 (br. s., 2 H) 7.04-7.13 (m, 1H) 7.30 (app. t, J=7.8 Hz, 2 H) 7.39-7.57 (m, 5 H) 7.65 (br. s., 1 H)7.80-7.91 (m, 2 H) 8.39 (t, J=6.0 Hz, 1 H) 9.60 (br.s., 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 44.2, 46.2, 74.3, 74.9, 78.2, 80.2, 122.9,124.1, 127.4, 128.3, 128.5, 131.3, 134.4, 139.4, 167.2, 180.7. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₄N₃O₄S⁺ 402.14820; Found 402.1469.

N-(((3S,4R,5R)-5-(acetamidomethyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(225)

General procedure 8. White foam, 91.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.79 (s, 3 H) 3.10 (app. dt, J=13.5, 6.4 Hz, 1 H) 3.32-3.48 (m, 3 H)3.48-3.57 (m, 2 H) 3.61 (app. td, J=7.3, 3.3 Hz, 1 H) 3.86 (d, J=9.4 Hz,1 H) 4.83 (br. s., 2 H) 7.40-7.57 (m, 3 H) 7.81-7.93 (m, 3 H) 8.34 (t,J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 22.5, 41.0, 44.3, 74.3,74.7, 78.0, 81.0, 127.3, 128.3, 131.3, 134.4, 167.1, 169.3. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₅H₂₁N₂O₅ ⁺ 309.14450; Found 309.1443.

N-(((3S,4R,5R)-3,4-dihydroxy-5-(pivalamidomethyl)tetrahydrofuran-3-yl)methyl)benzamide(226)

General procedure 8. White foam, quant. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.05 (s, 9 H) 3.17-3.44 (m, 4 H) 3.48-3.58 (m, 2 H) 3.62-3.69 (m, 1 H)3.82 (d, J=9.4 Hz, 1 H) 4.92 (br. s., 2 H) 7.34 (t, J=5.6 Hz, 1 H)7.42-7.57 (m, 3 H) 7.80-7.90 (m, 2 H) 8.35 (t, J=5.9 Hz, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 27.4, 38.0, 41.3, 44.1, 74.5, 74.6, 78.1, 80.9,127.3, 128.3, 131.3, 134.3, 167.0, 177.5. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₈H₂₇N₂O₅ ⁺ 351.19145; Found 351.1909.

N-(((3S,4R,5R)-5-((5-chloro-1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(227)

General procedure 8. White foam, 73.0% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.38-3.47 (m, 2 H) 3.51 (d, J=9.7 Hz, 1 H) 3.63-3.92 (m, 5 H) 4.82 (s, 1H) 5.04 (d, J=7.0 Hz, 1 H) 7.43-7.56 (m, 3 H) 7.78-7.97 (m, 5 H) 8.36(t, J=5.9 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 40.5, 44.0, 74.8,75.4, 78.2, 78.6, 123.2, 124.8, 127.3, 128.2, 130.1, 131.2, 133.5,134.2, 134.4, 139.3, 166.5, 166.8, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₁H₂₀ClN₂O₆ ⁺ 431.10044; Found 431.1018.

N-(((3S,4R,5R)-5-((benzylamino)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)benzamide(228)

General procedure 8. White foam, 83.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.08 (br. s., 1 H) 2.57 (dd, J=12.2, 6.3 Hz, 1 H) 2.73 (dd, J=12.2, 3.1Hz, 1 H) 3.36-3.47 (m, 2 H) 3.54 (d, J=9.4 Hz, 1 H) 3.59-3.74 (m, 4 H)3.85 (d, J=9.4 Hz, 1 H) 4.74 (s, 1 H) 4.90 (br. s., 1 H) 7.17-7.33 (m, 5H) 7.42-7.57 (m, 3 H) 7.81-7.88 (m, 2 H) 8.35 (t, J=6.0 Hz, 1 H). ¹³CNMR (75 MHz, DMSO-d₆) δ ppm 44.4, 50.8, 53.1, 74.4, 74.8, 77.9, 81.8,126.5, 127.3, 127.9, 128.1, 128.2, 131.2, 134.4, 140.8, 167.0. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₅N₂O₄ ⁺ 357.18088; Found 357.1804.

N-(((3S,4R,5R)-5-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)-N-methylbenzamide(229)

General procedure 8. White powder, 79.6% ¹H NMR (300 MHz, CDCl₃) δ ppm2.61 (s, 3 H) 3.26 (br. s., 2 H) 3.40 (br. s., 1 H) 3.59 (app. t., J=5.9Hz, 2H) 3.71 (d, J=10.0 Hz, 1 H) 4.14 (d, J=10.0 Hz, 1 H) 4.22 (app. q.,J=6.2 Hz, 1 H) 4.93 (d, J=6.7 Hz, 1 H) 6.21 (s, 1 H) 7.34-7.41 (m, 2 H)7.44-7.53 (m, 3 H) 7.63-7.70 (m, 1 H) 7.73-7.78 (m, 2 H) 7.96-8.02 (m, 2H) 8.66 (t, J=5.7 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 34.0, 41.1,53.9, 73.9, 76.1, 77.2, 79.4, 127.1, 128.2, 128.5, 129.3, 129.5, 131.1,133.5, 134.2, 165.4, 166.6. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₅N₂O₅ ⁺ 385.17580; Found 385.1766.

N-(((3S,4R,5R)-3,4-dihydroxy-5-((1-oxoisoindolin-2-yl)methyl)tetrahydrofuran-3-yl)methyl)benzamide(230)

General procedure 8. White foam, 84.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.49 (m, 2 H) 3.54-3.67 (m, 3 H) 3.78-3.93 (m, 3 H) 4.45-4.60 (2×d,J=18.2 Hz, 2 H) 4.77 (br. s., 2 H) 7.40-7.62 (m, 6 H) 7.65-7.71 (m, 1 H)7.78-7.85 (m, 2 H) 8.38 (t, J=5.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 44.1, 44.4, 51.0, 74.6, 74.8, 77.9, 81.0, 122.7, 123.3, 127.3,127.7, 128.2, 131.18, 131.22, 132.1, 134.4, 142.1, 167.1, 167.4. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₃N₂O₅ ⁺ 383.16015; Found 383.1610.

2-chloro-N-(((2R,3R,4S)-4-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(231)

General procedure 8. White powder, 82.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.64 (m, 4 H) 3.71-3.87 (m, 3 H) 3.98 (d, J=9.7 Hz, 1 H) 4.65 (s, 1H) 5.11 (d, J=7.0 Hz, 1 H) 7.30-7.48 (m, 4 H) 7.80-7.91 (m, 4 H) 8.45(t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.2, 42.3, 74.7,75.2, 77.9, 79.9, 123.0, 126.9, 128.9, 129.5, 129.8, 130.5, 131.8,134.3, 137.1, 166.5, 168.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₀ClN₂O₆ ⁺ 431.10044; Found 431.1005.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((4-methylbenzamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(232)

General procedure 8. White foam, 77.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.35 (s, 3 H) 3.29-3.60 (m, 5 H) 3.65 (d, J=7.9 Hz, 1 H) 3.71-3.81 (m, 1H) 3.87 (d, J=9.7 Hz, 1 H) 4.81 (br. s, 2 H) 7.27 (d, J=7.9 Hz, 2 H)7.30-7.48 (m, 4 H) 7.76 (app. d, J=8.2 Hz, 2 H) 8.28 (t, J=6.0 Hz, 1 H)8.45 (t, J=5.7 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 20.9, 41.3,44.2, 74.4, 74.7, 78.1, 80.6, 126.9, 127.3, 128.7, 128.9, 129.5, 129.9,130.5, 131.5, 137.0, 141.1, 166.5, 166.9. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₁H₂₄ClN₂O₅ ⁺ 419.13683, found 419.1368.

2-chloro-N-(((2R,3R,4S)-4-((4-fluorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(233)

General procedure 8. White powder, 82.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.54 (m, 4 H) 3.57 (d, J=9.7 Hz, 1 H) 3.62-3.69 (m, 1 H) 3.72-3.81(m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H) 5.01 (d, J=6.7 Hz, 1 H)7.25-7.49 (m, 6 H) 7.88-7.97 (m, 2 H) 8.40 (t, J=5.9 Hz, 1 H) 8.46 (t,J=5.7 Hz, 1 H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −109.5 (m). ¹³C NMR (75MHz, DMSO-d₆) δ ppm 41.3, 44.3, 74.4, 74.7, 78.0, 80.6, 115.1 (d, J=21.9Hz), 126.9, 128.9, 129.5, 129.9, 130.0 (d, J=9.2 Hz), 130.6, 130.9 (d,J=2.3 Hz), 137.0, 163.9 (d, J=248.8 Hz), 166.0, 166.5. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₀H₂₁ClFN₂O₆ ⁺ 423.11175, found 423.1122.

2-chloro-N-(((2R,3R,4S)-4-((4-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(234)

General procedure 8. White foam, 90.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.60 (m, 5 H) 3.61-3.69 (m, 1 H) 3.71-3.81 (m, 1 H) 3.87 (d, J=9.4Hz, 1 H) 4.86 (br. s., 2 H) 7.29-7.48 (m, 4 H) 7.51-7.57 (m, 2 H)7.83-7.94 (m, 2 H) 8.38-8.52 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm41.3, 44.3, 74.4, 74.7, 78.0, 80.6, 126.9, 128.3, 128.9, 129.3, 129.5,129.9, 130.5, 133.2, 136.0, 137.0, 166.0, 166.5. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₀H₂₁Cl₂N₂O₆ ⁺ 439.08220, found 439.0832.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((4-methoxybenzamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(235)

General procedure 8. White foam, 86.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.31-3.59 (m, 5 H) 3.62-3.68 (m, 1 H) 3.71-3.79 (m, 1 H) 3.81 (s, 3 H)3.87 (d, J=9.7 Hz, 1 H) 4.73 (br. s., 2 H) 6.94-7.04 (m, 2 H) 7.27-7.50(m, 4 H) 7.80-7.88 (m, 2 H) 8.23 (t, J=6.0 Hz, 1 H) 8.46 (t, J=5.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.2, 55.4, 74.4, 74.7, 78.1,80.6, 113.4, 126.5, 126.9, 128.9, 129.2, 129.5, 129.9, 130.5, 137.0,161.6, 166.47, 166.55. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₄ClN₂O₆⁺ 435.13174, found 435.1319.

2-chloro-N-(((2R,3R,4S)-4-((4-cyanobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(236)

General procedure 8. White foam, 81.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.55 (m, 4 H) 3.58 (d, J=9.7 Hz, 1 H) 3.62-3.70 (m, 1 H) 3.73-3.81(m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H) 5.05 (d, J=6.7 Hz, 1 H)7.29-7.48 (m, 4 H) 7.93-7.98 (m, 2 H) 7.98-8.04 (m, 2 H) 8.46 (t, J=5.7Hz, 1 H) 8.62 (t, J=5.9 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3,44.5, 74.4, 74.7, 77.9, 80.6, 113.5, 118.4, 126.9, 128.2, 128.9, 129.5,129.9, 130.6, 132.3, 137.0, 138.5, 165.7, 166.5. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₁H₂₁ClN₃O₅ ⁺ 430.11642, found 430.1175.

2-chloro-N-(((2R,3R,4S)-4-((4-(dimethylamino)benzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(237)

General procedure 8. White foam, 90.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.97 (s, 6 H) 3.33-3.58 (m, 5 H) 3.63 (d, J=7.9 Hz, 1 H) 3.71-3.80 (m, 1H) 3.86 (d, J=9.7 Hz, 1 H) 5.26 (br. s., 2 H) 6.66-6.75 (m, 2 H)7.29-7.49 (m, 4 H) 7.67-7.77 (m, 2 H) 8.05 (t, J=5.9 Hz, 1 H) 8.45 (t,J=5.7 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 39.8, 41.4, 44.2, 74.4,74.7, 78.2, 80.7, 110.8, 120.9, 126.9, 128.7, 128.9, 129.5, 129.9,130.5, 137.0, 152.1, 166.5, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₂H₂₇ClN₃O₆ ⁺ 448.16338, found 448.1623.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((4-(trifluoromethyl)benzamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(238)

General procedure 8. White powder, 90.5% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.56 (m, 4 H) 3.59 (d, J=9.7 Hz, 1 H) 3.64-3.70 (m, 1 H) 3.73-3.82(m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.85 (br. s., 2 H) 7.26-7.49 (m, 4 H)7.85 (app. d, J=8.2 Hz, 2 H) 8.06 (app. d, J=8.2 Hz, 2 H) 8.46 (t, J=5.6Hz, 1 H) 8.60 (t, J=5.9 Hz, 1 H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −61.3(s). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.4, 74.4, 74.8, 78.0, 80.6,124.0 (q, J=272.4 Hz), 125.3 (q, J=3.46 Hz), 126.9, 128.3, 128.9, 129.5,129.9, 130.5, 131.1 (q, J=31.7 Hz), 137.0, 138.3, 165.9, 166.5. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₁ClF₃N₂O₅ ⁺ 473.10856, found473.1092.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)isonicotinamide(239)

General procedure 8. White powder, 75.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.55 (m, 4 H) 3.58 (d, J=9.7 Hz, 1 H) 3.63-3.71 (m, 1 H) 3.73-3.82(m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H) 5.06 (d, J=6.7 Hz, 1 H)7.28-7.48 (m, 4 H) 7.74-7.79 (m, 2 H) 8.46 (t, J=5.6 Hz, 1 H) 8.65 (t,J=5.9 Hz, 1 H) 8.69-8.76 (m, 2H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.2,44.3, 74.4, 74.7, 77.9, 80.6, 121.4, 126.9, 128.9, 129.5, 129.9, 130.6,137.0, 141.4, 150.1, 165.4, 166.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₉H₂₁ClN₃O₆ ⁺ 406.11642, found 406.1175.

2-chloro-N-(((2R,3R,4S)-4-((3-fluorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(240)

General procedure 8. White powder, 92.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.55 (m, 4 H) 3.58 (d, J=9.7 Hz, 1 H) 3.63-3.70 (m, 1 H) 3.73-3.81(m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H) 5.03 (d, J=6.7 Hz, 1 H)7.27-7.48 (m, 5 H) 7.53 (app. td, J=8.0, 6.0 Hz, 1 H) 7.63-7.75 (m, 2 H)8.39-8.52 (m, 2 H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −113.0 (m). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 41.3, 44.4, 74.4, 74.7, 78.0, 80.6, 114.2 (d,J=23.0 Hz), 118.1 (d, J=21.9 Hz), 123.6 (d, J=2.3 Hz), 126.9, 128.9,129.5, 129.9, 130.4 (d, J=6.9 Hz), 130.6, 136.8 (d, J=6.9 Hz), 137.0,161.9 (d, J=244.1 Hz), 165.7 (d, J=2.3 Hz), 166.5. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₀H₂₁ClFN₂O₆ ⁺ 423.11175, found 423.1129.

2-chloro-N-(((2R,3R,4S)-4-((3-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(241)

General procedure 8. White powder, 59.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.60 (m, 5 H) 3.63-3.68 (m, 1 H) 3.72-3.81 (m, 1 H) 3.87 (d, J=9.7Hz, 1 H) 4.82 (br. s., 2 H) 7.27-7.54 (m, 5 H) 7.58-7.64 (m, 1 H) 7.82(app. dt, J=7.6, 1.3 Hz, 1 H) 7.91 (app. t, J=1.6 Hz, 1 H) 8.41-8.55 (m,2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.4, 74.4, 74.7, 78.0,80.6, 126.2, 126.9, 127.2, 128.9, 129.5, 129.9, 130.2, 130.5, 131.0,133.1, 136.4, 137.0, 165.6, 166.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₁Cl₂N₂O₆ ⁺ 439.08220, found 439.0820.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((3-(trifluoromethyl)benzamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(242)

General procedure 8. White foam, 89.6% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.56 (m, 4 H) 3.59 (d, J=9.4 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.74-3.82(m, 1 H) 3.89 (d, J=9.7 Hz, 1 H) 4.82 (br. s., 2 H) 7.27-7.48 (m, 4 H)7.73 (app. t, J=7.9 Hz, 1 H) 7.91 (app. d, J=7.9 Hz, 1 H) 8.12-8.24 (m,2 H) 8.46 (t, J=5.7 Hz, 1H) 8.67 (t, J=5.9 Hz, 1 H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ ppm −61.1 (s). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.4,74.4, 74.8, 78.0, 80.6, 124.02 (q, J=273.4 Hz), 124.03 (q, J=4.0 Hz),126.9, 127.8 (q, J=3.5 Hz), 128.9, 129.03 (q, J=31.9 Hz), 129.5, 129.6,129.9, 130.5, 131.5, 135.3, 137.0, 165.6, 166.5. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₁H₂₁ClF₃N₂O₅ ⁺ 473.10856, found 473.1096.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)nicotinamide(243)

General procedure 8. White powder, 58.6% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.55 (m, 4 H) 3.58 (d, J=9.7 Hz, 1 H) 3.63-3.71 (m, 1 H) 3.74-3.81(m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.77 (s, 1 H) 5.04 (d, J=6.7 Hz, 1 H)7.29-7.54 (m, 5 H) 8.16-8.23 (ddd, J=8.0, 2.2, 1.8 Hz, 1 H) 8.46 (t,J=5.7 Hz, 1 H) 8.58 (t, J=6.0 Hz, 1 H) 8.71 (app. dd, J=4.8, 1.6 Hz, 1H) 9.01 (app. dd, J=2.3, 0.9 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm41.3, 44.3, 74.4, 74.7, 78.0, 80.6, 123.4, 126.9, 128.9, 129.5, 129.9,130.0, 130.5, 135.1, 137.0, 148.5, 151.8, 165.6, 166.5. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₁₉H₂₁ClN₃O₆ ⁺ 406.11642, found 406.1175.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((2-methylbenzamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(244)

General procedure 8. White foam, 94.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.33 (s, 3 H) 3.33-3.43 (m, 3 H) 3.47-3.61 (m, 2 H) 3.62-3.69 (m, 1 H)3.71-3.82 (m, 1 H) 3.91 (d, J=9.7 Hz, 1 H) 4.75 (br. s, 2 H) 7.16-7.27(m, 2 H) 7.28-7.51 (m, 6 H) 8.14 (t, J=5.9 Hz, 1 H) 8.47 (t, J=5.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 19.4, 41.4, 44.1, 74.5, 74.8, 77.9,80.6, 125.4, 126.9, 127.1, 128.9, 129.3, 129.5, 129.9, 130.4, 130.6,135.2, 137.0, 137.1, 166.5, 169.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₄ClN₂O₅ ⁺ 419.13683, found 419.1374.

2-chloro-N-(((2R,3R,4S)-4-((2-fluorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)benzamide(245)

General procedure 8. White foam, 95.0% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.32-3.55 (m, 4 H) 3.58 (d, J=9.7 Hz, 1 H) 3.64-3.69 (m, 1 H) 3.72-3.82(m, 1 H) 3.87 (d, J=9.7 Hz, 1 H) 4.80 (br. s., 2 H) 7.21-7.60 (m, 7 H)7.61-7.72 (m, 1 H) 8.15 (dd, J=9.4, 5.6 Hz, 1 H) 8.47 (t, J=5.7 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ ppm −114.2 (m). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 41.4, 44.3, 74.5, 74.6, 77.7, 80.6, 116.1 (d, J=23.0 Hz),123.7 (d, J=15.0 Hz), 124.5 (d, J=3.5 Hz), 126.9, 128.9, 129.5, 129.9,130.3 (d, J=3.5 Hz), 130.6, 132.5 (d, J=9.2 Hz), 137.0, 159.2 (d,J=248.8 Hz), 164.1, 166.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₁ClFN₂O₅ ⁺ 423.11175, found 423.1132.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)furan-2-carboxamide(246)

General procedure 8. White foam, 83.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.57 (m, 5 H) 3.59-3.65 (m, 1 H) 3.72-3.80 (m, 1 H) 3.85 (d, J=9.7Hz, 1 H) 4.73 (br. s., 2 H) 6.63 (dd, J=3.2, 1.8 Hz, 1 H) 7.14 (dd,J=3.5, 0.9 Hz, 1 H) 7.30-7.48 (m, 4 H) 7.84 (dd, J=1.8, 0.9 Hz, 1 H)8.13 (t, J=6.0 Hz, 1 H) 8.45 (t, J=5.7 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 41.2, 43.5, 74.3, 74.7, 77.9, 80.5, 111.9, 113.7, 126.9,128.9, 129.5, 129.9, 130.5, 137.0, 145.1, 147.7, 158.3, 166.5. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₀ClN₂O₆ ⁺ 395.10044, found395.1005.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)furan-3-carboxamide(247)

General procedure 8. White foam, 79.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.29-3.58 (m, 5 H) 3.59-3.65 (m, 1 H) 3.72-3.80 (m, 1 H) 3.85 (d, J=9.7Hz, 1 H) 4.70 (br. s., 2 H) 6.88 (dd, J=1.9, 0.7 Hz, 1 H) 7.29-7.49 (m,4 H) 7.72 (app. t, J=1.8 Hz, 1 H) 8.14 (t, J=6.0 Hz, 1 H) 8.22 (dd,J=1.6, 0.7 Hz, 1 H) 8.46 (t, J=5.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δppm 41.3, 43.6, 74.2, 74.6, 78.1, 80.7, 109.1, 122.6, 126.9, 128.9,129.5, 129.9, 130.6, 137.0, 143.9, 145.3, 162.3, 166.5. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₁₈H₂₀ClN₂O₆ ⁺ 395.10044, found 395.1004.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)pyrimidine-5-carboxamide(248)

General procedure 8. White powder, 66.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.35-3.73 (m, 6 H) 3.74-3.81 (m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.79 (s, 1H) 5.08 (d, J=6.7 Hz, 1 H) 7.29-7.48 (m, 4 H) 8.46 (t, J=5.7 Hz, 1 H)8.77 (t, J=5.9 Hz, 1 H) 9.17 (app. s, 2 H) 9.31 (app. s, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 41.2, 44.3, 74.4, 74.7, 77.9, 80.7, 126.9,127.9, 128.9, 129.5, 129.8, 130.6, 137.0, 156.0, 160.0, 163.8, 166.5.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₀ClN₄O₅ ⁺ 407.11167, found407.1121.

N,N′-(((2R,3R,4S)-3,4-dihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(2-chlorobenzamide)(249)

General procedure 8. White foam, 94.8% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.26-3.48 (m, 3 H) 3.49-3.71 (m, 3 H) 3.74-3.82 (m, 1 H) 3.93 (d, J=9.7Hz, 1 H) 4.62 (br. s., 2 H) 7.31-7.52 (m, 8 H) 8.39 (t, J=5.9 Hz, 1 H)8.48 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.6, 43.9,74.5, 74.6, 77.9, 80.6, 126.9, 127.0, 128.96, 129.02, 129.51, 129.54,129.86, 129.91, 130.6, 130.7, 136.9, 137.0, 166.5, 166.9. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₀H₂₁Cl₂N₂O₅ ⁺ 439.08220; Found 439.0822.

N-(((2R,3R,4S)-4-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(250)

General procedure 8. White powder, 94.2% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.31-3.47 (m, 3 H) 3.56-3.69 (m, 3 H) 3.83 (app. dt, J=7.5, 3.7 Hz, 1 H)3.94 (d, J=9.7 Hz, 1 H) 4.74 (br. s., 2 H) 7.33-7.53 (m, 7 H) 7.70-7.79(m, 4 H) 7.94-8.00 (m, 2 H) 8.41 (t, J=6.0 Hz, 1 H) 8.56 (t, J=5.7 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.6, 44.2, 74.9, 75.1, 78.4, 81.1,126.9, 127.3, 127.4, 128.4, 129.42, 129.47, 130.0, 130.3, 131.2, 133.74,133.76, 137.3, 139.7, 143.0, 166.4, 167.3. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₂₆H₂₆ClN₂O₅ ⁺ 481.15248; Found 481.1532.

N-(((2R,3R,4S)-4-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyridazine-4-carboxamide(251)

General procedure 8. White foam, 87.9% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.34-3.49 (m, 3 H) 3.56-3.70 (m, 3 H) 3.81 (app. dt, J=7.5, 3.5 Hz, 1 H)3.94 (d, J=9.7 Hz, 1 H) 4.73 (s, 1 H) 5.08 (d, J=6.7 Hz, 1 H) 7.32-7.51(m, 4 H) 8.01 (dd, J=5.6, 2.3 Hz, 1 H) 8.41 (t, J=6.0 Hz, 1 H) 9.10 (t,J=5.6 Hz, 1 H) 9.41 (dd, J=5.3, 1.2 Hz, 1 H) 9.54 (dd, J=2.3, 1.2 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 42.1, 43.6, 74.4, 74.5, 77.9, 80.4,124.2, 127.0, 129.0, 129.5, 129.8, 130.7, 131.5, 136.9, 148.9, 152.1,163.4, 166.9. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₀ClN₄O₅ ⁺407.11167; Found 407.1114.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(252)

General procedure 8. White powder, 66.1% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.70 (m, 6 H) 3.74-3.82 (m, 1 H) 3.90 (d, J=9.7 Hz, 1 H) 4.89 (br.s, 2 H) 7.28-7.54 (m, 7 H) 7.70-7.80 (m, 4 H) 7.93-8.00 (m, 2 H)8.38-8.51 (m, 2H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.3, 44.3, 74.4,74.8, 78.1, 80.6, 126.46 (2C), 126.9, 128.03 (2C), 128.9, 129.0, 129.5,129.9, 130.5, 133.2, 137.0, 139.2, 142.8, 166.5, 166.7. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₆H₂₆ClN₂O₅ ⁺ 481.15248; Found 481.1513.

N-(((2R,3R,4S)-4-([1,1′-biphenyl]-4-carboxamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)pyridazine-4-carboxamide(253)

General procedure 8. White powder, 87.4% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.38-3.53 (m, 3 H) 3.54-3.71 (m, 3 H) 3.81 (app. td, J=7.3, 3.5 Hz, 1 H)3.91 (d, J=9.4 Hz, 1 H) 4.84 (br. s., 1 H) 5.04 (br. s., 1 H) 7.38-7.54(m, 3 H) 7.69-7.77 (m, 4 H) 7.93 (app. d, J=8.2 Hz, 2 H) 7.97 (dd,J=5.3, 2.3 Hz, 1 H) 8.44 (t, J=5.9 Hz, 1H) 9.09 (t, J=5.6 Hz, 1 H) 9.38(dd, J=5.3, 1.2 Hz, 1 H) 9.53 (dd, J=2.3, 1.2 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 41.9, 44.1, 74.4, 74.7, 78.1, 80.5, 124.2, 126.4, 126.9,127.97 (2 C), 129.0, 131.5, 133.1, 139.2, 142.8, 148.9, 152.0, 163.4,166.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₅N₄O₅ ⁺ 449.18195;Found 449.1801.

N-(((3S,4R,5R)-5-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)-[1,1′-biphenyl]-4-carboxamide(254)

General procedure 8. White powder, 81.0% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.44 (app. d, J=5.9 Hz, 2 H) 3.53 (d, J=9.7 Hz, 1 H) 3.64-3.96 (m, 5 H)4.84 (s, 1 H) 5.06 (d, J=6.7 Hz, 1 H) 7.38-7.54 (m, 3 H) 7.70-7.80 (m, 4H) 7.80-7.91 (m, 4 H) 7.92-7.98 (m, 2 H) 8.43 (t, J=5.9 Hz, 1 H). ¹³CNMR (75 MHz, DMSO-d₆) δ ppm 44.10 (2 C), 74.7, 75.6, 78.2, 78.6, 123.0,126.5, 126.9, 128.0, 129.0, 131.5, 133.2, 134.3, 134.4, 139.2, 142.8,166.7, 167.7. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₇H₂₅N₂O₆ ⁺473.17071; Found 473.1718.

N-(((3S,4R,5R)-5-((2-chlorobenzamido)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)pyridazine-4-carboxamide(255)

General procedure 8. White foam, 87.9% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.33-3.72 (m, 6 H) 3.72-3.82 (m, 1 H) 3.88 (d, J=9.7 Hz, 1 H) 4.80 (s, 1H) 5.10 (d, J=6.7 Hz, 1 H) 7.27-7.50 (m, 4 H) 8.01 (dd, J=5.3, 2.3 Hz, 1H) 8.46 (t, J=5.6 Hz, 1 H) 8.91 (t, J=5.9 Hz, 1 H) 9.43 (dd, J=5.3, 1.2Hz, 1 H) 9.55 (dd, J=2.3, 1.5 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm41.2, 44.4, 74.4, 74.7, 77.9, 80.6, 124.3, 126.9, 128.9, 129.5, 129.8,130.6, 131.6, 137.0, 148.9, 152.0, 163.9, 166.5. HRMS (ESI-TOF) m/z:[M+H]⁺ Calcd for C₁₈H₂₀ClN₄O₅ ⁺ 407.11167; Found 407.1100.

N-(((3S,4R,5R)-5-([1,1′-biphenyl]-4-carboxamidomethyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)pyridazine-4-carboxamide(256)

General procedure 8. White powder, 73.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.39-3.70 (m, 6 H) 3.83 (app. td, J=7.3, 3.7 Hz, 1 H) 3.89 (d, J=9.7 Hz,1 H) 4.80 (s, 1 H) 5.11 (d, J=6.7 Hz, 1 H) 7.36-7.45 (m, 1 H) 7.45-7.54(m, 2 H) 7.69-7.77 (m, 4 H) 7.94 (d, J=8.5 Hz, 2 H) 7.99 (dd, J=5.3, 2.3Hz, 1 H) 8.54 (t, J=5.6 Hz, 1 H) 8.92 (t, J=5.9 Hz, 1 H) 9.41 (dd,J=5.3, 1.2 Hz, 1 H) 9.55 (dd, J=2.3, 1.2 Hz, 1 H). ¹³C NMR (75 MHz,DMSO-d₆) δ ppm 41.9, 44.4, 74.6, 74.8, 77.9, 80.9, 124.3, 126.4, 126.8,127.94 (2 C), 129.0, 131.6, 133.3, 139.2, 142.6, 148.9, 152.0, 164.0,166.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₅N₄O₅ ⁺ 449.18195;Found 449.1829.

N,N′-(((2R,3R,4S)-3,4-dihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(pyridazine-4-carboxamide)(257)

General procedure 8. White powder, 77.3% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.37-3.53 (m, 3 H) 3.55-3.68 (m, 3 H) 3.76-3.84 (m, 1 H) 3.89 (d, J=9.7Hz, 1 H) 4.82 (s, 1 H) 5.16 (d, J=6.7 Hz, 1 H) 7.97 (dd, J=2.3, 1.2 Hz,1 H) 7.99 (dd, J=2.3, 1.2 Hz, 1 H) 8.91 (t, J=6.0 Hz, 1 H) 9.08 (t,J=5.7 Hz, 1 H) 9.38-9.43 (m, 2 H) 9.53 (app. td, J=2.5, 1.2 Hz, 2 H).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.9, 44.4, 74.6, 74.7, 77.8, 80.6,124.2, 124.3, 131.5, 131.6, 148.8, 148.9, 152.03 (2 C), 163.4, 163.9.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₆H₁₉N₆O₅ ⁺ 375.14114; Found375.1404.

N-(((3S,4R,5R)-5-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxytetrahydrofuran-3-yl)methyl)pyridazine-4-carboxamide(258)

General procedure 8. White powder, 65.7% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.37-3.56 (m, 3 H) 3.65-3.94 (m, 5 H) 4.82 (s, 1 H) 5.15 (d, J=6.7 Hz, 1H) 7.80-7.90 (m, 4 H) 7.99 (dd, J=5.3, 2.3 Hz, 1 H) 8.90 (t, J=6.0 Hz, 1H) 9.43 (dd, J=5.3, 1.2 Hz, 1 H) 9.54 (dd, J=2.3, 1.2 Hz, 1 H). ¹³C NMR(75 MHz, DMSO-d₆) δ ppm 40.3, 44.3, 74.7, 75.6, 78.0, 78.8, 123.0,124.3, 131.5, 131.6, 134.4, 148.9, 152.0, 164.0, 167.7. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₁₉H₁₉N₄O₆ ⁺ 399.12991; Found 399.1302.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((2-phenylacetamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(259)

General procedure 8. White foam, 84.8% ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.15 (dd, J=13.8, 5.6 Hz, 1 H) 3.20-3.59 (m, 7 H) 3.70-3.78 (m, 2 H)4.74 (br. s., 2 H) 7.17-7.49 (m, 9 H) 8.03 (t, J=5.7 Hz, 1 H) 8.46 (t,J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 41.4, 42.2, 43.8, 74.4,74.5, 77.9, 80.7, 126.3, 126.9, 128.2, 128.9, 129.0, 129.5, 129.9,130.6, 136.5, 137.0, 166.5, 170.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₁H₂₄ClN₂O₅ ⁺ 419.13683; Found 419.1366.

2-chloro-N-(((2R,3R,4S)-3,4-dihydroxy-4-((3-phenylpropanamido)methyl)tetrahydrofuran-2-yl)methyl)benzamide(260)

General procedure 8. White foam, 89.6% ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.37-2.46 (m, 2 H) 2.75-2.85 (m, 2 H) 3.14 (dd, J=13.8, 5.6 Hz, 1 H)3.23 (dd, J=13.8, 6.2 Hz, 1 H) 3.28-3.41 (m, 1 H) 3.42-3.57 (m, 3 H)3.64-3.78 (m, 2 H) 4.59 (br. s., 2 H) 7.13-7.50 (m, 9 H) 7.83 (t, J=5.9Hz, 1 H) 8.45 (t, J=5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 31.1,36.8, 41.4, 43.7, 74.4, 74.5, 77.9, 80.7, 125.8, 126.9, 128.17, 128.24,128.9, 129.5, 129.9, 130.6, 137.0, 141.3, 166.5, 172.0. HRMS (ESI-TOF)m/z: [M+H]⁺ Calcd for C₂₂H₂₆ClN₂O₅ ⁺ 433.15248; Found 433.1522.

N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-N-methylbenzamide(261)

General procedure 8. White foam, 97.8% ¹H NMR (300 MHz, DMSO-d₆) at 90°C. δ ppm 2.96 (s, 3 H) 3.38-3.71 (m, 6 H) 3.78-3.91 (m, 2 H) 4.36 (br.s., 2 H) 7.31-7.54 (m, 8 H) 7.78-7.84 (m, 2 H) 8.03 (br. s., 1 H). ¹³CNMR (75 MHz, DMSO-d₆) at 90° C. δ ppm 44.3, 51.7 (weak), 52.2 (weak),74.6, 74.9, 77.4, 80.6, 126.3, 126.7, 127.6, 127.7, 128.5, 130.6, 134.3,136.5, 166.9, 170.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₆ClN₂O₅ ⁺385.17580; Found 385.1770.

(3aS,6R,6aR)-3a,6-bis(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole(262)

To tosylate 23 (1.5 g, 4 mmol), dissolved in DMF (25 mL), was addedsodium azide (1.3 g, 20 mmol). After overnight reaction at 80° C., TLCanalysis (hexane/EtOAc 3:1) showed the presence of one major product.The solvent was evaporated and the residue was taken up in EtOAc (50mL). The resulting solution was washed with saturated sodium bicarbonatesolution and water. The organic layer was dried over sodium sulphate,filtered and concentrated in vacuo. This crude material was purified byflash column chromatography (hexane/EtOAc 9:1) to afford bisazide 262 asa colorless, transparant liquid in 85.5% yield. ¹H NMR (300 MHz, CDCl₃)δ ppm 1.48 (s, 3 H) 1.54 (s, 3 H) 3.38-3.51 (m, 3 H) 3.61 (d, J=13.2 Hz,1 H) 3.86-3.94 (m, 2 H) 4.21 (app. td, J=4.7, 2.3 Hz, 1 H) 4.41 (d,J=2.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.5, 28.1, 52.2, 54.2,75.8, 84.2, 85.0, 92.0, 115.2.

N,N′-(((3aS,6R,6aR)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxole-3a,6(4H)-diyl)bis(methylene))bis(3,4,5-tris(benzyloxy)benzamide)(263)

To a solution of bisazide 262 in THF (0.2 M) was added Me₃P (1M in THF,10 eq.) and the mixture was stirred for 2 h at rt. Water (100 μL permmol bisazide) was added and stirring was continued for 15 minutes. Themixture was taken to dryness and co-evaporated twice with toluene. Thecrude bisamine was taken up in DMF (to a concentration of 0.1 M). Addedare EDC.HCl (3.0 eq.), DMAP (1.0 eq.) HOBt (1.0 eq.) and the appropriatecarboxylic acid (2.5 eq.) and the mixture was stirred overnight. Themixture was taken to dryness, the residue was redissolved in EtOAc,transferred to a separatory funnel and washed successively with HCl (1M,twice) and NaHCO₃ (sat. aq., twice). The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by silicagel chromatography (CH2Cl₂/MeOH system) to yield the homobisbenzamide asa pale yellow foam (88.5%). ¹H NMR (300 MHz, CDCl3) δ ppm 1.32 (s, 3 H)1.49 (s, 3 H) 3.20-3.33 (m, 1 H) 3.52 (dd, J=14.2, 4.8 Hz, 1 H)3.81-3.96 (m, 3 H) 4.07 (dd, J=14.7, 8.2 Hz, 1 H) 4.20 (t, J=6.7 Hz, 1H) 4.58 (s, 1 H) 4.96 (s, 2 H) 4.98 (s, 2 H) 5.00 (s, 2 H) 5.01 (s, 2 H)5.02 (s, 2 H) 5.05 (s, 2 H) 7.19-7.37 (m, 34 H) 7.47 (t, J=6.0 Hz, 1 H)7.56 (t, J=6.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.7, 27.8, 39.9,42.8, 71.3 (br.), 74.7, 75.2 (br.), 84.1, 85.5, 92.2, 107.0, 107.1,113.3, 127.5, 127.6, 127.9, 128.0, 128.1, 128.2, 128.5 (v. br.), 128.8,129.0, 136.6, 136.7, 137.5 (br.), 141.4, 141.5, 152.8, 152.9, 167.6,167.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₆₅H₆₃N₂O₁₁ ⁺ 1047.44264;Found 1047.4473.

N,N′-(((2R,3R,4S)-3,4-dihydroxytetrahydrofuran-2,4-diyl)bis(methylene))bis(3,4,5-trihydroxybenzamide)(264)

A solution of bisbenzamide 263 (0.05 M) in MeOH was placed under a N₂atmosphere. Palladium black (20 mg/mmol bisbenzamide) was added and thereaction vessel was purged again with N₂. Hydrogen gas was bubbledthrough the solution for 2 h until all benzylethers were cleaved (MSanalysis). The vessel was purged with nitrogen gas, opened and thecontents were filtered over a Whatman fiberglass filter. Solution wasconcentrated in vacuo and redissolved in TFA (35% aq. solution) andstirred for 3 h. The solution was concentrated and the residue wasdissolved in a mixture of water and tBuOH (4:1 v/v). The mixture wasfrozen and lyophilized overnight yielding the product as an off whiteamorphous solid (quant.). ¹H NMR (300 MHz, CD₃OD) δ ppm 3.44-3.60 (m, 3H) 3.62-3.75 (m, 3 H) 3.87-3.94 (m, 1 H) 3.97 (d, J=9.7 Hz, 1 H) 6.86(s, 2 H) 6.87 (s, 2H); ¹³C NMR (75 MHz, CD₃OD) δ ppm 43.2, 46.3, 76.4,76.6, 79.9, 83.0, 108.0, 108.1, 125.9, 126.2, 138.2, 138.4, 146.7,146.8, 170.9, 171.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂N₂O₁₁ ⁺467.12964; Found 467.1300.

(3aR,6S,6aR)-6-(hydroxymethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one(265)

To a solution of 2,3-O-isopropylidene-D-ribonolactone (24.5 g, 130.0mmol) and triethylamine (36.2 mL, 260.0 mmol) in CH₂Cl₂ (650 mL) stirredat 0° C., methanesulfonyl chloride (12.1 mL, 156.0 mmol) was addeddropwise under a nitrogen atmosphere. The reaction mixture was allowedto attain ambient temperature. After 3 hours, TLC analysis(toluene/EtOAc 3:2) showed complete consumption of the startingmaterial. The reaction mixture was washed with saturated sodiumbicarbonate solution and water. The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo to afford the mesylate as ayellow to orange colored oil. To this crude mesylate, dissolved in1,4-dioxane (600 mL), was added a solution of KOH (21.9 g, 390.0 mmol)in 300.0 mL of water. This solution was stirred vigorously for 3 h. Whencomplete, the pH was adjusted to 3 by adding 1M HCl (270 mL). The acidicsolution was concentrated in vacuo to afford a solid mass, that wastriturated with acetone (250 mL) and heated to reflux (20 minutes at 70°C.). The acetone was decanted and filtered. The remaining solid mass wastriturated 2 more times and each time the boiling acetone was decantedand filtered. The combined clear filtrate was concentrated in vacuo toyield 2,3-O-isopropylidene-L-Lyxonolactone as a colorless oil (64.8%).¹H NMR (300 MHz, (CD₃)₂CO) δ ppm 1.34 (s, 3 H) 1.37 (s, 3 H) 3.83 (dd,J=12.0, 7.0 Hz, 1 H) 3.91 (dd, J=12.0, 10.3 Hz, 1 H) 4.15 (br. s., 1 H)4.65 (ddd, J=7.1, 4.9, 2.9 Hz, 1 H) 4.93-5.02 (m, 2 H). ¹³C NMR (75 MHz,CDCl₃) δ ppm 26.0, 27.0, 60.9, 77.2, 77.3, 80.6, 113.9, 174.6. HRMS(ESI-TOF) m/z: [M+H]⁺ Calcd for C₈H₁₃O₅ ⁺ 189.07575; Found 189.0766.

(3aR,6S,6aR)-6-(azidomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one(266)

To a dry and cooled (0° C.) solution of2,3-O-isopropylidene-L-Lyxonolactone (4.0 g, 21.3 mmol) in CH₂Cl₂ (150mL) were subsequently added Et₃N (5.9 mL, 42.5 mmol) and MsCl (2.0 mL,25.5 mmol). The resulting reaction mixture was stirred for 3 h, afterwhich time TLC analysis showed completion. The reaction mixture wastransferred to a sep. fun., diluted with CH₂Cl₂, washed with sat. aq.NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated. The residuewas taken up in DMF (200 mL). Next, NaN₃ (5.5 g, 85.0 mmol) was addedand the reaction mixture was stirred overnight at 90° C. When complete,volatile organics were evaporated. The residue was diluted with EtOAcand washed with water and brine. Purification via FCC (toluene/EtOAc7:3) yielded the title compound as a yellow to orange colored liquid(80.8%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (s, 3 H) 1.49 (s, 3 H)3.61-3.76 (m, 2 H) 4.58 (ddd, J=7.0, 6.2, 3.2 Hz, 1 H) 4.81-4.90 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 25.9, 26.8, 49.8, 75.8, 76.1, 77.3,114.7, 173.1.

(3aR,6S,6aR)-6-(azidomethyl)-3a-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(267)

Azidolactone 266 (10.8 g, 50.7 mmol) was dissolved in CH₂Cl₂ (130 mL)and cooled to −78° C. This solution was flushed with nitrogen gas, afterwhich a solution of diisobutylaluminium hydride (1M in toluene, 55.5 mL,55.5 mmol) was added dropwise. The cooled solution was allowed to reactfor 4 hours under nitrogen. The reaction was quenched by adding EtOAc(10 mL) and the mixture was allowed to come to room temperature over 30min, after which a saturated Na⁺/K⁺ tartrate solution (300 mL) wasadded. The mixture was stirred for another hour and extracted with EtOAc(4×250 mL). The combined organic layers were dried (sodium sulphate),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (hexane/EtOAc 3:1) to afford 10.5 g of a pale oil.The azidolactole (10.0 g, 46.5 mmol) was dissolved in 350 mL of MeOH.Potassium carbonate (3.2 g, 23.3 mmol) and an aqueous solution offormaldehyde (38%, 110 mL) were added. The reaction mixture was stirredfor 24 h at 50° C. TLC analysis showed presence of a major product. Thereaction mixture was cooled to ambient temperature and the MeOH wasevaporated under reduced pressure. The residual aqueous solution wasextracted with EtOAc (3×250 mL). The organic layers were combined, driedover sodium sulphate, filtered and concentrated. The residue waspurified by flash chromatography (CH₂Cl₂/MeOH 98:2) to afford compound267 as a white powder (46.1% over two steps). Data in accordance withSimone et al.

((R)-5-((S)-2-azido-1-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4,4-diyl)dimethanol(268)

Sodium borohydride (0.36 g, 9.6 mmol) was added to a stirred and cooled(0° C.) solution of compound 267 (0.78 g, 3.2 mmol) in MeOH (30 mL). Thereaction mixture was allowed to attain ambient temperature and wasstirred overnight. Ammonium chloride (1.85 g) was added to quench theexcess of borohydride. The resulting suspension was stirred for 2 h,concentrated and adsorbed onto celite. Purification by flashchromatography afforded triol 268 as a white powder in 24.2% yield(81.9% based on recovered SM). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.37 (s, 3H) 1.46 (s, 3 H) 3.34-3.52 (m, 2 H) 3.58-3.70 (m, 4 H) 3.99-4.06 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 26.8, 28.4, 55.9, 63.0, 64.4, 69.6,80.2, 85.1, 109.1.

(3aS,6S,6aR)-3a,6-bis(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole(269)

To a stirred solution of triol 268 (0.32 g, 1.3 mmol) in pyridine (15mL) was added p-toluenesulfonylchloride (0.53 g, 2.8 mmol). The reactionmixture was stirred at room temperature for 3 h and then heated to 60°C. to let it react overnight. The resulting suspension was filtered andthe residue was concentrated under reduced pressure. The crude materialwas then purified by flash column chromatography (hexane/EtOAc 4:1) toafford 180 mg of a colorless oil, which was subsequently taken up in DMF(10 mL). Next, NaN₃ was added (0.15 g, 2.35 mmol) and the reactionmixture was stirred overnight at 80° C. TLC analysis (hexane/EtOAc 3:1)showed the presence of one major product. The solvent was evaporated andthe residue was taken up in EtOAc. The resulting solution was washedwith saturated sodium bicarbonate solution and water. The organic layerwas dried over sodium sulphate, filtered and concentrated in vacuo. Thismaterial was purified by flash column chromatography (hexane/EtOAc 9:1)to afford 269 as a pale oil (29.4% over two steps). ¹H NMR (300 MHz,CDCl₃) δ ppm 1.46 (s, 3 H) 1.51 (s, 3 H) 3.42-3.61 (m, 5 H) 3.66-3.73(m, 1 H) 3.98-4.04 (m, 2 H).). ¹³C NMR (75 MHz, CDCl₃) δ ppm 27.47 (2C), 49.7, 54.2, 76.0, 81.2, 83.8, 92.3, 114.5.

N,N′-(((2S,3R,4S)-3,4-dihydroxytetrahydrofuran-2,4-diyl)bis(methylene))dibenzamide(270)

To a solution of bisazide 269 in THF (0.2 M) was added Me₃P (1M in THF,10 eq.) and the mixture was stirred for 3 h at rt. Water (100 μL permmol bisazide) was added and stirring was continued for 45 minutes. Themixture was taken to dryness and co-evaporated twice with toluene. Thecrude bisamine was taken up in DMF (to a concentration of 0.1 M). Addedare EDC.HCl (3.0 eq.), DMAP (1.0 eq.) HOBt (1.0 eq.) and benzoic acid(2.5 eq.) and the mixture was stirred overnight. The mixture was takento dryness, the residue was redissolved in EtOAc, transferred to aseparatory funnel and washed successively with HCl (1M, twice) andNaHCO₃ (sat. aq., twice). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by silica gelchromatography (Toluene/EtOAc system). A solution of the obtainedbisbenzamide was dissolved in TFA (35% aq. solution) and stirred for 3h. The solution was concentrated and the residue was purified by HPLC(H2O/MeCN 9:1 to 0:1) to yield homobisbenzamide 270 as a white foam(74.3% over two steps). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.33-3.69 (m, 6H) 3.96 (app. t, J=5.0 Hz, 1 H) 4.13 (app. dt, J=7.4, 4.8 Hz, 1 H) 4.99(s, 1 H) 5.24 (d, J=5.0 Hz, 1 H) 7.41-7.57 (m, 6 H) 7.82-7.89 (m, 4 H)8.40-8.50 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 44.50 (2 C), 72.4,73.2, 79.1, 79.6, 127.2, 127.3, 128.23 (2 C), 131.1, 131.2, 134.3,134.5, 166.3, 167.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₃N₂O₆ ⁺371.16015; Found 371.1588.

Methyl 2-(bromomethyl)benzoate (271)

A mixture of Methyl 2-methylbenzoate (1 mL, 7.2 mmol) and NBS (1.4 g,7.9 mmol) in CCl₄ (28 mL) was degassed. AIBN (24 mg, 0.14 mmol) wasadded and the mixture was heated to 85° C. overnight. Further NBS (0.13g, 0.71 mmol) was added and the whole was refluxed for 1 more hour. Themixture was diluted with CH₂Cl₂ and washed with sat. aq. NaHCO₃ solutionand water. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flashchromatography (hexane/EtOAc 100:0→95:5) gave the title compound as anorange to pink liquid that solidifies on standing (67.6%). ¹H NMR (300MHz, CDCl₃) δ ppm 3.92 (s, 3 H) 4.95 (s, 2 H) 7.30-7.39 (m, 1 H)7.41-7.53 (m, 2 H) 7.89-8.01 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ ppm31.7, 52.4, 128.7, 129.2, 131.4, 131.8, 132.7, 139.4, 167.2.

Compounds 1 to 3 were synthesized according to the procedure describedin Simone, Edwards et al. 2008.

Compounds 22 and 23 were synthesized according to the proceduredescribed in Bouisset, Gosselin et al. 2008.

C. In Vitro and In Vivo Assays

C.1. Determination of the minimal inhibitory effect:

Minimum inhibitory concentrations (MICs) of the hamamelitannin analogswere determined in triplicate according to the EUCAST brothmicrodilution protocol, using flat-bottom 96-well microtiter plates(TPP, Trasadingen, Switzerland). The inoculum was standardized toapproximately 5×10⁵ CFU/ml. The plates were incubated at 37° C. for 20h, and the optical density at 590 nm was determined by using amultilabel microtiter plate reader (Envision; Perkin-Elmer LAS, Waltham,Mass.). The lowest concentration of the compounds for which a similaroptical density was observed in the inoculated and the blank wells wasrecorded as the MIC MIC values were observed to be higher than thehighest concentration tested (MIC>500 μM).

C.2. Effect of pre-treatment and combined treatment on biofilmsusceptibility:

The compounds were evaluated for their effect on biofilm susceptibilityboth under pre-treatment and combination treatment regimens. In thepre-treatment regimen, a methicillin resistant S. aureus Mu50 strain (S.aureus ATCC700699) was allowed to form biofilms in the presence of thecompounds after which the biofilm was treated with vancomycin (20μg/ml). In the combination treatment regimen, S. aureus Mu50 was allowedto form a mature biofilm after which it was treated with a combinationof a compound and vancomycin. In brief, 100 μl of a standardizedinoculum (10⁸ CFU/ml) was placed in the wells of a round-bottom 96-wellmicrotiter plate. The cells were allowed to adhere to the plate in theabsence (combined treatment) or presence (pre-treatment) of thecompounds (0.1-250 μM) for 4 h at 37° C. After this adhesion step,non-adhered cells were removed, the wells were rinsed and fresh mediumwith or without the compounds was added. The plates were incubated foran additional 20 h at 37° C. After this, the medium was removed,biofilms were rinsed with physiological saline and vancomycin (20 μg/ml)was added alone (pre-treatment) or with the compounds (combinedtreatment, 0.1-250 μM). Plates were placed at 37° C. for 24 h afterwhich medium was removed, wells were rinsed and the surviving cells ineach condition were collected. The number of surviving cells under eachcondition was compared to vancomycin treatment alone and was assessed byconventional plating. Results of these experiments are presented inTable 1. The REF compound (hamamelitannin) was also observed for itseffect on biofilm susceptibility towards other antibiotics (incl.vancomycin, cefoxitin, tobramycin, cefazolin, cefalonium, daptomycin,linezolide and cephalexin). Biofilms were formed as described above andwere treated with the antibiotics alone or in combination with the REFcompound (250 μM). The number of surviving cells under each conditionwas compared to the untreated control biofilm and was assessed byconventional plating. Results of these experiments are presented in FIG.3.

C.3. The effect on in vivo survival of infected c. elegans nematodes:

The in vivo effect of treatment with the compound alone (FIG. 1) or acombined treatment with a compound and vancomycin (FIG. 2) was evaluatedusing a C. elegans model system (Brackman et al., 2011). In brief, asuspension of synchronized worms (L4 stage) was divided into 24-wellplates containing no bacteria or S. aureus Mu50 cells (2.5×10⁷ CFU). Thenematodes received no treatment, a treatment with vancomycin alone orvancomycin in combination with a compound. The fraction of dead wormswas determined 48 h post-infection by counting the number of dead wormsand the total number of worms in each condition using a dissectingmicroscope.

C.4. The in vivo effect of treatment with the compound alone or acombined treatment with a compound and cefalexin (FIG. 4) was evaluatedusing a murine intramammary S. aureus infection model, i.e. a model ofS. aureus mastitis infection (Demon et al., 2012). In brief, CD-1lactating mice (Harlan Laboratories Inc., Netherlands) were utilized12-14 days after birth of the offspring. The pups were weaned 1-2 hbefore bacterial inoculation of the mammary glands. A mixture of oxygenand isoflurane (2-3%) was used for inhalational anesthesia of thelactating mice. A syringe with 32-gauge blunt needle (ThiebaudBiomedical Devices, France) was applied to inoculate both L4 (on theleft) and R4 (on the right) glands of the fourth abdominal mammary glandpair with approximately 150 CFU of S. aureus. Each orifice was exposedby a small cut at the near end of the teat and 100 μl of the inoculumwas injected slowly through the teat canal. The formulations containingREF, compound 171, cefalexin or a combination of cefalexin and REF orcompound 171 were instilled into the mammary gland of anesthetized miceusing the desired dose (μg/gland) at 4 h after bacterial inoculation.Immediately thereafter the postoperative analgesic Buprecare (CodifarNV, Belgium) was administered intraperitoneally, i.e. at 4 h afterbacterial inoculation. All groups were composed of 5 mice (10 mammaryglands). After sacrifice of the mice by cervical dislocation at 14 hpost-treatment, mammary glands (two per mouse) were harvested, weighedand homogenized on ice in sterile PBS using a tissue ruptor (QIAGENBenelux BV, Netherlands). The mammary glands, which are structurallyseparate, were considered as individual samples. Bacterial CFU countswere obtained by standard plating.

Results of the above assays are detailed in the following table andfigures.

TABLE 1 Effect of pre-treatment and combined treatment on biofilmsusceptibility. Pretreat. Combin. Pretreat Combin. (EC50) (EC50) N^(o)Structure (100 μM)^(a) (100 μM)^(a) (μM)^(b) (μM)^(b) REF

43.35 43.15 145.5  166.6   8

 9

 10

 11

 12

 13

 14

 15

22.35 57.74 63.82 191.1   16

62.41 71.85 207.4  238.1   17

55.76 61.16 182.1  168.9   18

37.58 79.55 115.8  230.6   19

19.78 27.23 38.53 52.31  20

19.78 27.23 85.56 52.31  21

18.04 56.02 73.63 154.2   34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

150

151

22.36 24.59 152

15.07 14.05 153

 9.185  8.577 18.01 21.39 154

19.34 22.56 155

15.57 16.06 156

16.58 11.27 157

15.95 11.25 158

 7.268 13.89  9.943 19.16 159

10.97  6.966  6.379 11.32 160

23.09 23.39 161

 9.353 16.57 162

24.07 29.06 163

28.44 27.21 164

22.11 14.49 165

16.00 26.43 166

10.16 12.34  9.135 12.27 167

 9.813 15.22 168

 9.830 32.61 169

11.68 13.87 13.67 52.62 170

11.84 16.30 171

11.56  7.776   0.3890  7.976 172

15.37 31.40 173

11.18  8.805  5.013  8.298 174

28.01 11.11 175

22.48 34.85 176

21.56 36.02 177

15.07 13.23 178

4.10 17.51  9.845 19.74 179

3.84 16.46  1.855 20.38 180

79.13 65.66 181

67.74 59.09 182

42.13 33.81 183

60.04 61.60 184

33.91 40.23 185

22.11 36.32 186

41.45 42.75 187

32.91 29.24 188

34.36 34.64 189

59.77 58.95 190

64.43 29.24 191

32.28 19.28 192

31.41 43.74 59.24 136.2  193

10.80 11.25 11.37 11.74 194

20.50 13.31 195

18.31 18.55  7.203  9.261 196

21.86  8.072 12.97  7.876 197

18.75 16.84  7.919  8.268 198

19.18 11.25 10.78  7.517 199

68.76 65.56 >250   >250   200

58.59 48.93 >250   232.3  201

51.81 74.81 199.6  >250   202

14.00 18.24 203

41.20 31.95 204

13.04 15.85 205

 6.699 16.51 206

 6.460 15.17 207

 6.950 13.70  7.279  8.535 208

10.52 18.77 209

22.47 21.74 29.33 23.48 210

22.10 26.95 52.34 58.24 211

31.02 38.03 212

50.68 52.64 213

28.32 32.67 214

29.28 42.85 215

22.23 31.29 216

16.96 25.95 217

14.04 14.85 23.46 27.78 218

35.03 26.88 219

16.13 17.02 220

25.63 29.85 221

54.01 33.81 222

47.10 73.90 223

23.99 18.72 224

20.22 27.33 225

23.96 27.38 226

50.74 28.64 227

77.57 61.81 228

18.68 22.13 41.2  45.2  229

 7.17 11.15  5.820  8.920 230

24.90 30.15 57.70 60.20 231

 8.18 28.85  2.632 38.97 249

 6.67 13.59  5.357 28.42 250

18.82 29.48 23.04 61.29 251

 3.85 37.03  3.376 98.93 252

 2.25 29.40 11.84 69.17 253

 4.25 22.50  8.537 45.40 254

 3.52 30.44  4.793 57.12 255

 8.03 25.78 14.95 55.71 256

14.25 29.97 15.46 53.39 257

 1.71 17.13  7.135 17.98 258

 0.73 23.56  5.853 11.41 259

55.12 71.25 260

57.01 71.12 261

 6.09 10.02  8.499 24.29 263

264

22.35 57.74 63.82 191.1  270

51.80 55.70 224   >250   Pretreat Combin. Pretreat. Combin. (EC50)(EC50) N^(o) Structure (25 μM)^(a) (25 μM)^(a) (μM)^(b) (μM)^(b) REF

61.63 65.94 145.5  166.6  232

52.41 42.16 79.69 41.88 233

88.61 91.63 234

61.12 56.96 235

66.10 57.35 236

73.00 70.73 237

58.79 47.56 47.63 69.73 238

45.03 68.51 84.56 75.23 239

49.98 58.76 240

118.37  91.32 241

98.17 81.35 242

117.15  87.14 243

85.00 51.83 244

41.07 54.77 56.44 123.6  245

61.75 44.14 48.56 62.18 246

87.98 62.82 247

42.14 49.94 68.47 76.65 248

64.01 65.41 ^(a)percentage Colony Forming Units (CFU's) per biofilm whenbiofilms are treated with VAN alone (20 μg/ml) or in combination withHAM or a HAM- analogue compared to the untreated (negative) control.^(b)EC₅₀ values are expressed as the concentration of the analogueneeded to get 50% killing of the bacteria compared to treatment withantibiotic alone (general activity of the antibiotic) and completekilling (max activity). REF = hamamelitannin

REFERENCES

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The invention claimed is:
 1. A compound of Formula I,

Wherein X is selected from N—R₉, O and S—R₉; R₁ is selected from—C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and —SO₂—R₁₅; wherein said—C₁₋₆alkyl may be further substituted with —R₂₄; R₂ is selected from —Hand —C₁₋₆alkyl, or R₁ taken together with R₂ forms Het₃; R₃ is absent orselected from —H, —OH, and -halo; R₄ is selected from —H, —OH, and-halo; or R₃ taken together with R₄ forms a dioxolane moiety, which isoptionally substituted with from 1 to 3 substituents selected from —OH,—C₁₋₆alkyl, and -halo; R₅ is selected from —H, —OH, ═O, and -halo; R₆ isselected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,and —CN; R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁,and —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with—R₂₅; R₈ is selected from —H and —C₁₋₆alkyl; or R₇ taken together withR₈ forms Het₄; R₉ is selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl,—(C═O)—Ar₃ and —Ar₃ when X is N; absent when X is O; or absent orselected from ═O, and —O₂ when X is S; R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ areeach independently selected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁,Het₁, —NH—C₁₋₆alkyl, —NH—Het₁ and —NH—Ar₁; wherein each of said—C₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—CN, —NR₁₆R₁₇, —C₃₋₆cycloalkyl, -Het₁ and —Ar₁; R₁₀, R₁₁ and R₁₂ areeach independently selected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₂,Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of said —C₁₋₆alkyl isoptionally substituted with from 1 to 3 substituents selected from ═O,—OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl,-Het₂ and —Ar₂; R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are eachindependently selected from —H, and —C₁₋₆alkyl; Ar₁, Ar₂, Ar₃, Ar₄ andAr₅ are each independently a 5-10 membered aromatic mono- or bicycle;wherein each of said Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ is optionally andindependently substituted with from 1 to 3 substituents selected from═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁, and-phenyl; wherein said phenyl is optionally substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, or —NR₂₀R₂₁; Het₁, Het₂, Het₃ and Het₄ are each independentlya 5-10 membered mono- or bicyclic heteroaryl comprising from 1 to 3heteroatoms selected from N, O and S; wherein each of said Het₁, Het₂,Het₃ and Het₄ is optionally and independently substituted with from 1 to3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionallysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.
 2. A compoundaccording to claim 1, Wherein X is selected from N—R₉, O and S—R₉; R₁ isselected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and —SO₂—R₁₅;wherein said —C₁₋₆alkyl may be further substituted with —R₂₄; R₂ isselected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂ formsHet₃; R₃ taken together with R₄ forms a dioxolane moiety, which isoptionally substituted with from 1 to 3 substituents selected from —OH,—C₁₋₆alkyl, and -halo; R₅ is selected from —H, —OH, ═O, and -halo; R₆ isselected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,and —CN; R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁,and —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with—R₂₅; R₈ is selected from —H and —C₁₋₆alkyl; or R₇ taken together withR₈ forms Het₄; R₉ is selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl,—(C═O)—Ar₃ and —Ar₃ when X is N; absent when X is O; or absent orselected from ═O, and —O₂ when X is S; R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ areeach independently selected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁,Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and —NH—Ar₁; wherein each of said—C₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—CN, —NR₁₆R₁₇, —C₃₋₆cycloalkyl, -Het₁ and —Ar₁; R₁₀, R₁₁ and R₁₂ areeach independently selected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₂,Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of said —C₁₋₆alkyl isoptionally substituted with from 1 to 3 substituents selected from ═O,—OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl,-Het₂ and —Ar₂; R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are eachindependently selected from —H, and —C₁₋₆alkyl; Ar₁, Ar₂, Ar₃, Ar₄ andAr₅ are each independently a 5-10 membered aromatic mono- or bicycle;wherein each of said Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ is optionally andindependently substituted with from 1 to 3 substituents selected from═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₀R₂₁, and-phenyl; wherein said phenyl is optionally substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, or —NR₂₀R₂₁; Het₁, Het₂, Het₃ and Het₄ are each independentlya 5-10 membered mono- or bicyclic heteroaryl comprising from 1 to 3heteroatoms selected from N, O and S; wherein each of said Het₁, Het₂,Het₃ and Het₄ is optionally and independently substituted with from 1 to3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl is optionallysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.
 3. A compoundaccording to claim 1, Wherein X is selected from N—R₉, O and S—R₉; R₁ isselected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and —SO₂—R₁₅;wherein said —C₁₋₆alkyl may be further substituted with —R₂₄; R₂ isselected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂ formsHet₃; R₃ is —OH; R₄ is —OH; R₅ is selected from —H, —OH, ═O, and -halo;R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, and —CN; R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀,—(C═S)—R₁₁, and —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be furthersubstituted with —R₂₅; R₈ is selected from —H and —C₁₋₆alkyl; or R₇taken together with R₈ forms Het₄; R₉ is selected from —H, —C₁₋₆alkyl,—(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and —Ar₃ when X is N; absent when X is O;or absent or selected from ═O, and —O₂ when X is S; R₁₃, R₁₄, R₁₅, R₂₄,and R₂₅ are each independently selected from —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and —NH—Ar₁;wherein each of said —C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇, —C₃₋₆cycloalkyl, -Het₁ and—Ar₁; R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of said—C₁₋₆alkyl is optionally substituted with from 1 to 3 substituentsselected from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉,—C₃₋₆cycloalkyl, -Het₂ and —Ar₂; R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ andR₂₃ are each independently selected from —H, and —C₁₋₆alkyl; Ar₁, Ar₂,Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ isoptionally and independently substituted with from 1 to 3 substituentsselected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃,—NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally substitutedwith from 1 to 3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁; Het₁, Het₂, Het₃ and Het₄ are eachindependently a 5-10 membered mono- or bicyclic heteroaryl comprisingfrom 1 to 3 heteroatoms selected from N, O and S; wherein each of saidHet₁, Het₂, Het₃ and Het₄ is optionally and independently substitutedwith from 1 to 3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl isoptionally substituted with from 1 to 3 substituents selected from ═O,—OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.
 4. Acompound according to claim 1, Wherein X is selected from N—R₉, O andS—R₉; R₁ is selected from —C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and—SO₂—R₁₅; wherein said —C₁₋₆alkyl may be further substituted with —R₂₄;R₂ is selected from —H and —C₁₋₆alkyl, or R₁ taken together with R₂forms Het₃; R₃ is absent or selected from —H, —OH, and -halo; R₄ isselected from —H, —OH, and -halo; or R₃ taken together with R₄ forms adioxolane moiety, which is optionally substituted with from 1 to 3substituents selected from —OH, —C₁₋₆alkyl, and -halo; R₅ is selectedfrom —H, —OH, ═O, and -halo; R₆ is —H; R₇ is selected from —C₁₋₆alkyl,—Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁, and —SO₂—R₁₂; wherein said —C₁₋₆alkyl maybe further substituted with —R₂₅; R₈ is selected from —H and —C₁₋₆alkylor R₇ taken together with R₈ forms Het₄; R₉ is selected from —H,—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—Ar₃ and —Ar₃ when X is N; absentwhen X is O; or absent or selected from ═O, and —O₂ when X is S; R₁₃,R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —Ar₁, Het₁, —NH—C₁₋₆alkyl, —NH-Het₁ and —NH—Ar₁;wherein each of said —C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇, —C₃₋₆cycloalkyl, -Het₁ and—Ar₁; R₁₀, R₁₁ and R₁₂ are each independently selected from —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and —NH—Ar₂; wherein each of said—C₁₋₆alkyl is optionally substituted with from 1 to 3 substituentsselected from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉,—C₃₋₆cycloalkyl, -Het₂ and —Ar₂; R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ andR₂₃ are each independently selected from —H, and —C₁₋₆alkyl; Ar₁, Ar₂,Ar₃, Ar₄ and Ar₅ are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ isoptionally and independently substituted with from 1 to 3 substituentsselected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃,—NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionally substitutedwith from 1 to 3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁; Het₁, Het₂, Het₃ and Het₄ are eachindependently a 5-10 membered mono- or bicyclic heteroaryl comprisingfrom 1 to 3 heteroatoms selected from N, O and S; wherein each of saidHet₁, Het₂, Het₃ and Het₄ is optionally and independently substitutedwith from 1 to 3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl isoptionally substituted with from 1 to 3 substituents selected from ═O,—OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.
 5. Acompound according to claim 1, Wherein X is O; R₁ is selected from—C₁₋₆alkyl, —Ar₄, —(C═O)—R₁₃, —(C═S)—R₁₄, and —SO₂—R₁₅; wherein said—C₁₋₆alkyl may be further substituted with —R₂₄; R₂ is selected from —Hand —C₁₋₆alkyl, or R₁ taken together with R₂ forms Het₃; R₃ is absent orselected from —H, —OH, and -halo; or R₃ taken together with R₄ forms adioxolane moiety, which is optionally substituted with from 1 to 3substituents selected from —OH, —C₁₋₆alkyl, and -halo; R₄ is selectedfrom —H, —OH, and -halo; R₅ is selected from —H, —OH, ═O, and -halo; R₆is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,and —CN; R₇ is selected from —C₁₋₆alkyl, —Ar₅, —(C═O)—R₁₀, —(C═S)—R₁₁,and —SO₂—R₁₂; wherein said —C₁₋₆alkyl may be further substituted with—R₂₅; R₈ is selected from —H and —C₁₋₆alkyl or R₇ taken together with R₈forms Het₄; R₉ is absent; R₁₃, R₁₄, R₁₅, R₂₄, and R₂₅ are eachindependently selected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₁, Het₁,—NH—C₁₋₆alkyl, —NH-Het₁ and —NH—Ar₁; wherein each of said —C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from ═O, —OH, -halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —CN, —NR₁₆R₁₇,—C₃₋₆cycloalkyl, -Het₁ and —Ar₁; R₁₀, R₁₁ and R₁₂ are each independentlyselected from —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —Ar₂, Het₂, —NH-Het₂ and—NH—Ar₂; wherein each of said —C₁₋₆alkyl is optionally substituted withfrom 1 to 3 substituents selected from ═O, —OH, -halo, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —CN, —NR₁₈R₁₉, —C₃₋₆cycloalkyl, -Het₂ and —Ar₂; R₁₆, R₁₇,R₁₈, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are each independently selected from —H,and —C₁₋₆alkyl; Ar₁, Ar₂, Ar₃, Ar₄ and Ar₅ are each independently a 5-10membered aromatic mono- or bicycle; wherein each of said Ar₁, Ar₂, Ar₃,Ar₄ and Ar₅ is optionally and independently substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, —NR₂₀R₂₁, and -phenyl; wherein said phenyl is optionallysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₀R₂₁; Het₁, Het₂, Het₃ andHet₄ are each independently a 5-10 membered mono- or bicyclic heteroarylcomprising from 1 to 3 heteroatoms selected from N, O and S; whereineach of said Het₁, Het₂, Het₃ and Het₄ is optionally and independentlysubstituted with from 1 to 3 substituents selected from ═O, —OH, -halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein saidphenyl is optionally substituted with from 1 to 3 substituents selectedfrom ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —CF₃, or —NR₂₂R₂₃.6. A compound according to claim 1, Wherein X is O; R₁ is selected from—C₁₋₆alkyl, —(C═O)—R₁₃, —(C═S)—R₁₄, and —SO₂—R₁₅; wherein said—C₁₋₆alkyl may be further substituted with —R₂₄; R₂ is —H; or R₁ takentogether with R₂ forms Het₃; R₃ is selected from —H, and —OH; or R₃taken together with R₄ forms a dioxolane moiety, which is optionallysubstituted with from 1 to 3 —C₁₋₆alkyl substituents; R₄ is —OH; R₅ is—H; R₆ is selected from —H, and —OH; R₇ is selected from —C₁₋₆alkyl, and(C═O)—R₁₀; wherein said —C₁₋₆alkyl may be further substituted with —R₂₅;R₈ is —H; or R₇ taken together with R₈ forms Het₄; R₉ is absent; R₁₃,R₁₄, R₁₅, R₂₄, and R₂₅ are each independently selected from —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each of said—C₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo and —Ar₁; R₁₀, is independentlyselected from —C₁₋₆alkyl, —Ar₂, and Het₂; wherein each of said—C₁₋₆alkyl is optionally substituted with from 1 to 3 substituentsselected halo and Ar₂; R₂₀, and R₂₁, are each independently selectedfrom —H, and —C₁₋₆alkyl; Ar₁, and Ar₂, are each independently a 5-10membered aromatic mono- or bicycle; wherein each of said Ar₁, and Ar₂,is optionally and independently substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, —NR₂₀R₂₁, and -phenyl; Het₁, Het₂, Het₃ and Het₄ are eachindependently a 5-10 membered mono- or bicyclic heteroaryl comprisingfrom 1 to 3 heteroatoms selected from N, O and S; wherein each of saidHet₁, Het₂, Het₃ and Het₄ is optionally and independently substitutedwith from 1 to 3 substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —CN, —CF₃, —NR₂₂R₂₃, and -phenyl; wherein said phenyl isoptionally substituted with from 1 to 3 substituents selected from ═O,—OH, -halo, —C₁₋₆alkyl, and phenyl.
 7. A compound according to claim 1,Wherein X is O; R₁ is selected from —C₁₋₆alkyl, (C═O)—R₁₃, and —SO₂—R₁₅;wherein said —C₁₋₆alkyl may be further substituted with —R₂₄; R₂ is H;or R₁ taken together with R₂ forms Het₃; R₃ and R₄ are —OH; or R₃ takentogether with R₄ forms a dioxolane moiety, which is optionallysubstituted with from 1 to 3 —C₁₋₆alkyl substituents; R₅ is —H; R₆ isselected from —H, and —OH; R₇ is selected from —C₁₋₆alkyl, and—(C═O)—R₁₀; wherein said —C₁₋₆alkyl may be further substituted with—R₂₅; R₈ is —H; or R₇ taken together with R₈ forms Het₄; R₉ is absent;R₁₃, R₁₅, R₂₄, and R₂₅ are each independently selected from —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —Ar₁, Het₁, and —NH—Ar₁; wherein each of said—C₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo and —Ar₁; R₁₀, is independentlyselected from —Ar₂, and Het₂; R₂₀, and R₂₁, are each independentlyselected from —H, and —C₁₋₆alkyl; Ar₁, and Ar₂, are each independently a5-10 membered aromatic mono- or bicycle; wherein each of said Ar₁, andAr₂, is optionally and independently substituted with from 1 to 3substituents selected from ═O, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—CN, —CF₃, —NR₂₀R₂₁, and -phenyl; Het₁, Het₂, and Het₃ are eachindependently a 5-10 membered mono- or bicyclic heteroaryl comprisingfrom 1 to 3 heteroatoms selected from N, O and S; wherein each of saidHet₁, Het₂, and Het₃ is optionally and independently substituted withfrom 1 to 3 substituents selected from ═O, —OH, -halo, and -phenyl.
 8. Acompound according to claim 1, wherein the compound has thestereoisomeric configuration as represented in formula II:


9. A compound according to claim 1 or a stereoisomer, tautomer, racemic,salt, hydrate, or solvate thereof, and optionally a metabolite, pre- orprodrug thereof.
 10. A combination of a compound as defined in claim 1with an antimicrobial agent.
 11. A pharmaceutical composition comprisinga compound as defined in claim 1 and a pharmaceutically acceptableexcipient, diluent and/or carrier.
 12. A pharmaceutical compositionaccording to claim 11, wherein said pharmaceutical composition isadministered orally, systemically or topically.
 13. A medical devicecomprising one or more compounds according to claim
 1. 14. A medicaldevice according to claim 13, wherein said device is selected from thegroup consisting of grafts, membranes, tubes, connectors, surgicalinstruments, intra-aortic balloons, stents, blood bags, catheters,sutures, prostheses, heart valves, tissue adhesives, cardiac pacemakerleads, artificial organs, lenses for the eye, blood handling equipment,apheresis equipment, bio sensors, dental devices, skin patches, wounddressings, implantable devices, tampons, bandages, drug deliverysystems, bodily implants, and protein-eluting scaffolds for tissueregeneration.
 15. A medical device according to claim 13, wherein theone or more compounds is formulated in or applied on the device.
 16. Amethod for the reduction and/or treatment of a bacterial infectionand/or biofilm formation in a subject in need thereof, said methodcomprising administering a therapeutic effective amount of a compound asdefined in claim 1 to said subject.
 17. The method according to claim16, wherein the infection is a Staphylococcus aureus infection.
 18. Themethod according to claim 16, said method resulting in the reductionand/or treatment of wound infections, skin ulcers, diabetic foot ulcers,burn wound infections, catheter-associated infections, stent-associatedinfections, infections resulting from animal bites, mastitis, pneumoniaor sepsis.